Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation
Abstract
1. Introduction
2. Characteristics and Nomenclature of Macrophages
2.1. The Origin of Macrophages
2.2. Classification and Morphological Characteristics of Macrophages
2.3. General Functions of Macrophages
3. Colon and Rectal Macrophages in Physiology
4. Characteristics of Tumor-Associated Macrophages (TAMs) in CRC
4.1. Regulatory Factors of TAMs in CRC
4.1.1. Selected Proteins and Extracellular Vesicles (EVs)
4.1.2. Non-Coding RNAs (ncRNAs)
4.1.3. Components of the Colonic Microbiota and Natural Bioactive Compounds
5. Clinical Role of TAMs in Colorectal Cancer
5.1. In Vitro Studies
5.2. Animal Models
5.3. In Vivo Studies
6. Therapies Targeting TAMs in CRC
7. SRIF System as Regulator of the Macrophages
7.1. Somatostatin (SST)
Somatostatin (SST) Expression in Macrophages
7.2. Somatostatin Receptors (SSTRs, SST1-5)
Somatostatin Receptor (SSTR) Expression in Macrophages
7.3. SST/SSA Actions in the Monocytes/Macrophages
7.4. Macrophages and SRIF System in CRC—A Gap to Be Filled
7.5. SRIF System and TAM Interactions in CRC Diagnosis and Therapy
8. Concluding Remarks and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AC | adenylate/adenylyl cyclase |
AMPK | adenosine monophosphate-activated protein kinase |
CAC | colitis-associated colorectal cancer |
CCL2/17/20/22 | C-C motif chemokine ligand 2/17/20/22 |
CD | Crohn’s disease |
CMS1/4 | consensus molecular subtype 1/4 |
COLEC12 | collectin subfamily member 12 |
CST | cortistatin |
CRC | colorectal cancer |
CXCL1/10 | C-X-C motif chemokine ligand 1/10 |
DCs | dendritic cells |
DFS | disease-free survival |
DSS | dextran sodium sulfate |
EECs | enteroendocrine cells |
EGF(R) | epidermal growth factor (receptor) |
ERK1/2 | extracellular signal-regulated kinase 1/2 |
EV | extracellular vesicle |
IBD | inflammatory bowel disease |
IGF | insulin-like growth factor |
IHC | immunohistochemistry |
IL-1β/4/6/6R/12/13 | interleukin 1 beta/4/6/6 Receptor/12/13, etc. |
IL-4I1 | interleukin-4-induced gene 1 |
IFN-γ | interferon γ |
iNOS (NOS2) | inducible nitric oxide synthase (nitric oxide synthase 2) |
LYVE1 | lymphatic vessel endothelial hyaluronan receptor 1 |
Mφ | macrophage |
M-CSF | macrophage colony-stimulating factor |
MAPK | mitogen-activated protein kinase (originally called ERK) |
MARCO | macrophage receptor with collagenous structure |
MHC-II | major histocompatibility complex proteins class II |
MPS | mononuclear phagocyte system |
MRC1 | mannose receptor C-type 1 |
MSI | microsatellite instability |
NE/NET | neuroendocrine/neuroendocrine tumor |
OCT | octreotide |
OS | overall survival |
PBMCs | peripheral blood mononuclear cells |
PDGF(R) | platelet-derived growth factor (receptor) |
PI3K/AKT | phosphoinositide 3-kinase/serine/threonine kinase Akt |
SIRPα | signal regulatory protein α |
SRIF/SRIH/SST | somatotropin-release inhibitory factor/hormone/somatostatin |
SSAs | somatostatin analogs |
SSTRs (SST1-5) | somatostatin receptors (1-5) |
STAT3/6 | signal transducer and activator of transcription 3/6 |
TAMs | tumor-associated macrophages |
TME | tumor microenvironment |
TGF-β1 | transforming growth factor-beta 1 |
TNBS | trinitrobenzene sulfonic acid |
TNF-α | tumor necrosis factor-alpha |
TRMs | tissue-resident macrophages |
UC | ulcerative colitis |
VEGF(A) | vascular endothelial growth factor (A) |
References
- Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J. Clin. 2024, 74, 229–263. [Google Scholar] [CrossRef] [PubMed]
- Patel, S.G.; Karlitz, J.J.; Yen, T.; Lieu, C.H.; Boland, C.R. The rising tide of early-onset colorectal cancer: A comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol. Hepatol. 2022, 7, 262–274. [Google Scholar] [CrossRef] [PubMed]
- Sung, H.; Siegel, R.L.; Laversanne, M.; Jiang, C.; Morgan, E.; Zahwe, M.; Cao, Y.; Bray, F.; Jemal, A. Colorectal cancer incidence trends in younger versus older adults: An analysis of population-based cancer registry data. Lancet Oncol. 2025, 26, 51–63. [Google Scholar] [CrossRef] [PubMed]
- Kather, J.N.; Halama, N. Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer. Br. J. Cancer 2019, 120, 871–882. [Google Scholar] [CrossRef]
- Ugai, T.; Väyrynen, J.P.; Lau, M.C.; Borowsky, J.; Akimoto, N.; Väyrynen, S.A.; Zhao, M.; Zhong, R.; Haruki, K.; Costa, A.D.; et al. Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer. Cancer Immunol. Immunother. 2022, 71, 933–942. [Google Scholar] [CrossRef]
- Zhong, X.; Chen, B.; Yang, Z. The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression. Cell. Physiol. Biochem. 2018, 45, 356–365. [Google Scholar] [CrossRef]
- Wang, H.; Tian, T.; Zhang, J. Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis. Int. J. Mol. Sci. 2021, 22, 8470. [Google Scholar] [CrossRef]
- Li, Y.; Chen, Z.; Han, J.; Ma, X.; Zheng, X.; Chen, J. Functional and Therapeutic Significance of Tumor-Associated Macrophages in Colorectal Cancer. Front. Oncol. 2022, 12, 781233. [Google Scholar] [CrossRef]
- Roelands, J.; Kuppen, P.J.K.; Vermeulen, L.; Maccalli, C.; Decock, J.; Wang, E.; Marincola, F.M.; Bedognetti, D.; Hendrickx, W. Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications. Int. J. Mol. Sci. 2017, 18, 2229. [Google Scholar] [CrossRef]
- Li, Q.; Geng, S.; Luo, H.; Wang, W.; Mo, Y.Q.; Luo, Q.; Wang, L.; Song, G.B.; Sheng, J.P.; Xu, B. Signaling pathways involved in colorectal cancer: Pathogenesis and targeted therapy. Signal Transduct. Target. Ther. 2024, 9, 266. [Google Scholar] [CrossRef]
- Ma, Z.; Williams, M.; Cheng, Y.Y.; Leung, W.K. Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer. Dis. Markers 2019, 2019, 2673543. [Google Scholar] [CrossRef] [PubMed]
- Ramírez-Perdomo, A.; Márquez-Barrios, G.; Gutiérrez-Castañeda, L.D.; Parra-Medina, R. Neuroendocrine Peptides in The Pathogenesis of Colorectal Carcinoma. Exp. Oncol. 2023, 45, 3–16. [Google Scholar] [CrossRef] [PubMed]
- Dai, X.; Sun, X.; Wu, Y.; Lv, Z.; Yu, Z.; Yuan, Y.; Sun, L. Site-Specific Hypermethylation of SST 1stExon as a Biomarker for Predicting the Risk of Gastrointestinal Tract Cancers. Dis. Markers 2022, 2022, 4570290. [Google Scholar] [CrossRef]
- Kasprzak, A. Somatostatin and Its Receptor System in Colorectal Cancer. Biomedicines 2021, 9, 1743. [Google Scholar] [CrossRef]
- Günther, T.; Tulipano, G.; Dournaud, P.; Bousquet, C.; Csaba, Z.; Kreienkamp, H.J.; Lupp, A.; Korbonits, M.; Castaño, J.P.; Wester, H.J.; et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol. Rev. 2018, 70, 763–835. [Google Scholar] [CrossRef]
- Weinstock, J.V.; Elliott, D. The substance P and somatostatin interferon-gamma immunoregulatory circuit. Ann. N. Y. Acad. Sci. 1998, 840, 532–539. [Google Scholar] [CrossRef]
- ten Bokum, A.M.; Hofland, L.J.; van Hagen, P.M. Somatostatin and somatostatin receptors in the immune system: A review. Eur. Cytokine Netw. 2000, 11, 161–176. [Google Scholar] [PubMed]
- Krantic, S. Peptides as regulators of the immune system: Emphasis on somatostatin. Peptides 2000, 21, 1941–1964. [Google Scholar] [CrossRef]
- Ganea, D.; Delgado, M. Inhibitory neuropeptide receptors on macrophages. Microbes Infect. 2001, 3, 141–147. [Google Scholar] [CrossRef]
- Francelin, C.; Veneziani, L.P.; Farias, A.D.S.; Mendes-da-Cruz, D.A.; Savino, W. Neurotransmitters Modulate Intrathymic T-Cell Development. Front. Cell Dev. Biol. 2021, 9, 668067. [Google Scholar] [CrossRef]
- Taniyama, Y.; Suzuki, T.; Mikami, Y.; Moriya, T.; Satomi, S.; Sasano, H. Systemic distribution of somatostatin receptor subtypes in human: An immunohistochemical study. Endocr. J. 2005, 52, 605–611. [Google Scholar] [CrossRef] [PubMed]
- Pintér, E.; Helyes, Z.; Szolcsányi, J. Inhibitory effect of somatostatin on inflammation and nociception. Pharmacol. Ther. 2006, 112, 440–456. [Google Scholar] [CrossRef] [PubMed]
- Armani, C.; Catalani, E.; Balbarini, A.; Bagnoli, P.; Cervia, D. Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages. J. Leukoc. Biol. 2007, 81, 845–855. [Google Scholar] [CrossRef] [PubMed]
- Ferone, D.; Pivonello, R.; Kwekkeboom, D.J.; Gatto, F.; Ameri, P.; Colao, A.; de Krijger, R.R.; Minuto, F.; Lamberts, S.W.J.; van Hagen, P.M.; et al. Immunohistochemical localization and quantitative expression of somatostatin receptors in normal human spleen and thymus: Implications for the in vivo visualization during somatostatin receptor scintigraphy. J. Endocrinol. Invest. 2012, 35, 528–534. [Google Scholar] [CrossRef]
- Wang, F.; Deng, Y.; Yu, L.; Zhou, A.; Wang, J.T.; Jia, J.Y.; Li, N.; Ding, F.D.; Lian, W.; Liu, Q.C.; et al. A Macrophage Membrane-Polymer Hybrid Biomimetic Nanoplatform for Therapeutic Delivery of Somatostatin Peptide to Chronic Pancreatitis. Pharmaceutics 2022, 14, 2341. [Google Scholar] [CrossRef]
- Guo, Z.; Xing, Z.; Cheng, X.; Fang, Z.; Jiang, C.; Su, J.; Zhou, Z.; Xu, Z.; Holmberg, A.; Nilsson, S.; et al. Somatostatin Derivate (smsDX) Attenuates the TAM-Stimulated Proliferation, Migration and Invasion of Prostate Cancer via NF-κB Regulation. PLoS ONE 2015, 10, e0124292. [Google Scholar] [CrossRef]
- Lapa, C.; Linsenmann, T.; Lückerath, K.; Samnick, S.; Herrmann, K.; Stoffer, C.; Ernestus, R.I.; Buck, A.K.; Löhr, M.; Monoranu, C.M. Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy? PLoS ONE 2015, 10, e0122269. [Google Scholar] [CrossRef]
- Schiavo Lena, M.; Partelli, S.; Castelli, P.; Andreasi, V.; Smart, C.E.; Pisa, E.; Bartolomei, M.; Bertani, E.; Zamboni, G.; Falconi, M.; et al. Histopathological and Immunophenotypic Changes of Pancreatic Neuroendocrine Tumors after Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT). Endocr. Pathol. 2020, 31, 119–131. [Google Scholar] [CrossRef]
- Locati, M.; Curtale, G.; Mantovani, A. Diversity, Mechanisms, and Significance of Macrophage Plasticity. Annu. Rev. Pathol. 2020, 15, 123–147. [Google Scholar] [CrossRef]
- Kadomoto, S.; Izumi, K.; Mizokami, A. Macrophage Polarity and Disease Control. Int. J. Mol. Sci. 2021, 23, 144. [Google Scholar] [CrossRef]
- Miah, M.; Goh, I.; Haniffa, M. Prenatal Development and Function of Human Mononuclear Phagocytes. Front. Cell Dev. Biol. 2021, 9, 649937. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Stokes, J.V.; Tan, W.; Pruett, S.B. An optimized flow cytometry panel for classifying macrophage polarization. J. Immunol. Methods 2022, 511, 113378. [Google Scholar] [CrossRef] [PubMed]
- Lendeckel, U.; Venz, S.; Wolke, C. Macrophages: Shapes and functions. ChemTexts 2022, 8, 12. [Google Scholar] [CrossRef]
- Mackowiak, P.A. Recycling metchnikoff: Probiotics, the intestinal microbiome and the quest for long life. Front. Public Health. 2013, 1, 52. [Google Scholar] [CrossRef]
- Gordon, S. Elie Metchnikoff, the Man and the Myth. J. Innate Immun. 2016, 8, 223–227. [Google Scholar] [CrossRef]
- van Furth, R.; Sluiter, W. Current views on the ontogeny of macrophages and the humoral regulation of monocytopoiesis. Trans. R. Soc. Trop. Med. Hyg. 1983, 77, 614–619. [Google Scholar] [CrossRef]
- Ginhoux, F.; Guilliams, M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 2016, 44, 439–449. [Google Scholar] [CrossRef]
- Blériot, C.; Chakarov, S.; Ginhoux, F. Determinants of Resident Tissue Macrophage Identity and Function. Immunity 2020, 52, 957–970. [Google Scholar] [CrossRef]
- Park, M.D.; Silvin, A.; Ginhoux, F.; Merad, M. Macrophages in health and disease. Cell 2022, 185, 4259–4279. [Google Scholar] [CrossRef]
- Sawai, C.M.; Babovic, S.; Upadhaya, S.; Knapp, D.J.H.F.; Lavin, Y.; Lau, C.M.; Goloborodko, A.; Feng, J.; Fujisaki, J.; Ding, L.; et al. Hematopoietic Stem Cells are the Major Source of Multilineage Hematopoiesis in Adult Animals. Immunity 2016, 45, 597–609. [Google Scholar] [CrossRef]
- Bajpai, G.; Schneider, C.; Wong, N.; Bredemeyer, A.; Hulsmans, M.; Nahrendorf, M.; Epelman, S.; Kreisel, D.; Liu, Y.; Itoh, A.; et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 2018, 24, 1234–1245. [Google Scholar] [CrossRef] [PubMed]
- Mu, X.; Li, Y.; Fan, G.C. Tissue-Resident Macrophages in the Control of Infection and Resolution of Inflammation. Shock 2021, 55, 14–23. [Google Scholar] [CrossRef] [PubMed]
- Gordon, S.; Plüddemann, A. Tissue macrophages: Heterogeneity and functions. BMC Biol. 2017, 15, 53. [Google Scholar] [CrossRef] [PubMed]
- Ryter, A. Relationship between ultrastructure and specific functions of macrophages. Comp. Immunol. Microbiol. Infect. Dis. 1985, 8, 119–133. [Google Scholar] [CrossRef]
- Mills, C.D.; Kincaid, K.; Alt, J.M.; Heilman, M.J.; Hill, A.M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 2000, 164, 6166–6173. [Google Scholar] [CrossRef]
- Mantovani, A.; Sica, A.; Sozzani, S.; Allavena, P.; Vecchi, A.; Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25, 677–686. [Google Scholar] [CrossRef]
- Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front. Biosci. 2008, 13, 453–461. [Google Scholar] [CrossRef]
- Colin, S.; Chinetti-Gbaguidi, G.; Staels, B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 2014, 262, 153–166. [Google Scholar] [CrossRef]
- Wang, L.X.; Zhang, S.X.; Wu, H.J.; Rong, X.L.; Guo, J. M2b macrophage polarization and its roles in diseases. J. Leukoc. Biol. 2019, 106, 345–358. [Google Scholar] [CrossRef]
- Gao, J.; Liang, Y.; Wang, L. Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy. Front. Immunol. 2022, 13, 888713. [Google Scholar] [CrossRef]
- McWhorter, F.Y.; Wang, T.; Nguyen, P.; Chung, T.; Liu, W.F. Modulation of macrophage phenotype by cell shape. Proc. Natl. Acad. Sci. USA 2013, 110, 17253–17258. [Google Scholar] [CrossRef] [PubMed]
- Hu, G.; Su, Y.; Kang, B.H.; Fan, Z.; Dong, T.; Brown, D.R.; Cheah, J.; Wittrup, K.D.; Chen, J. High-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming. Nat. Commun. 2021, 12, 773. [Google Scholar] [CrossRef] [PubMed]
- Shiratori, H.; Feinweber, C.; Luckhardt, S.; Wallner, N.; Geisslinger, G.; Weigert, A.; Parnham, M.J. An in vitro test system for compounds that modulate human inflammatory macrophage polarization. Eur. J. Pharmacol. 2018, 833, 328–338. [Google Scholar] [CrossRef]
- Selig, M.; Poehlman, L.; Lang, N.C.; Völker, M.; Rolauffs, B.; Hart, M.L. Prediction of six macrophage phenotypes and their IL-10 content based on single-cell morphology using artificial intelligence. Front. Immunol. 2024, 14, 1336393. [Google Scholar] [CrossRef]
- Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969, Erratum in: Nat. Rev. Immunol. 2010, 10, 460. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.; Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.; Sahebkar, A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 2018, 233, 6425–6440. [Google Scholar] [CrossRef]
- Hume, D.A.; Millard, S.M.; Pettit, A.R. Macrophage heterogeneity in the single-cell era: Facts and artifacts. Blood 2023, 142, 1339–1347. [Google Scholar] [CrossRef]
- Shin, A.E.; Tesfagiorgis, Y.; Larsen, F.; Derouet, M.; Zeng, P.Y.F.; Good, H.J.; Zhang, L.; Rubinstein, M.R.; Han, Y.W.; Kerfoot, S.M.; et al. F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis. Gastroenterology 2023, 164, 593–609.e13. [Google Scholar] [CrossRef]
- Yin, T.; Li, X.; Li, Y.; Zang, X.; Liu, L.; Du, M. Macrophage plasticity and function in cancer and pregnancy. Front. Immunol. 2024, 14, 1333549. [Google Scholar] [CrossRef]
- Katkar, G.; Ghosh, P. Macrophage states: There’s a method in the madness. Trends Immunol. 2023, 44, 954–964. [Google Scholar] [CrossRef]
- Li, C.; Xu, M.M.; Wang, K.; Adler, A.J.; Vella, A.T.; Zhou, B. Macrophage polarization and meta-inflammation. Transl. Res. 2018, 191, 29–44. [Google Scholar] [CrossRef] [PubMed]
- Su, P.; Li, O.; Ke, K.; Jiang, Z.; Wu, J.; Wang, Y.; Mou, Y.; Jin, W. Targeting tumor-associated macrophages: Critical players in tumor progression and therapeutic strategies (Review). Int. J. Oncol. 2024, 64, 60. [Google Scholar] [CrossRef] [PubMed]
- Chanmee, T.; Ontong, P.; Konno, K.; Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014, 6, 1670–1690. [Google Scholar] [CrossRef] [PubMed]
- Hourani, T.; Holden, J.A.; Li, W.; Lenzo, J.C.; Hadjigol, S.; O’Brien-Simpson, N.M. Tumor Associated Macrophages: Origin, Recruitment, Phenotypic Diversity, and Targeting. Front. Oncol. 2021, 11, 788365. [Google Scholar] [CrossRef]
- Nagashima, R.; Maeda, K.; Imai, Y.; Takahashi, T. Lamina propria macrophages in the human gastrointestinal mucosa: Their distribution, immunohistological phenotype, and function. J. Histochem. Cytochem. 1996, 44, 721–731. [Google Scholar] [CrossRef]
- Viola, M.F.; Boeckxstaens, G. Niche-specific functional heterogeneity of intestinal resident macrophages. Gut 2021, 70, 1383–1395. [Google Scholar] [CrossRef]
- Domanska, D.; Majid, U.; Karlsen, V.T.; Merok, M.A.; Beitnes, A.R.; Yaqub, S.; Bækkevold, E.S.; Jahnsen, F.L. Single-cell transcriptomic analysis of human colonic macrophages reveals niche-specific subsets. J. Exp. Med. 2022, 219, e20211846. [Google Scholar] [CrossRef]
- Fritsch, S.D.; Sukhbaatar, N.; Gonzales, K.; Sahu, A.; Tran, L.; Vogel, A.; Mazic, M.; Wilson, J.L.; Forisch, S.; Mayr, H.; et al. Metabolic support by macrophages sustains colonic epithelial homeostasis. Cell Metab. 2023, 35, 1931–1943.e8. [Google Scholar] [CrossRef]
- Chikina, A.S.; Matic Vignjevic, D.; Lennon-Dumenil, A.M. Roles of the macrophages in colon homeostasis. C. R. Biol. 2021, 344, 337–356. [Google Scholar] [CrossRef]
- Van den Bossche, J. Colonic macrophages eat and feed. Cell Metab. 2023, 35, 1847–1848. [Google Scholar] [CrossRef]
- Nakanishi, S.; Mantani, Y.; Ohno, N.; Morishita, R.; Yokoyama, T.; Hoshi, N. Histological study on regional specificity of the mucosal nerve network in the rat large intestine. J. Vet. Med. Sci. 2023, 85, 123–134. [Google Scholar] [CrossRef] [PubMed]
- Murase, S.; Mantani, Y.; Ohno, N.; Shimada, A.; Nakanishi, S.; Morishita, R.; Yokoyama, T.; Hoshi, N. Regional differences in the ultrastructure of mucosal macrophages in the rat large intestine. Cell Tissue Res. 2024, 396, 245–253. [Google Scholar] [CrossRef] [PubMed]
- Ye, L.; Zhang, T.; Kang, Z.; Guo, G.; Sun, Y.; Lin, K.; Huang, Q.; Shi, X.; Ni, Z.; Ding, N.; et al. Tumor-Infiltrating Immune Cells Act as a Marker for Prognosis in Colorectal Cancer. Front. Immunol. 2019, 10, 2368. [Google Scholar] [CrossRef]
- Edin, S.; Wikberg, M.L.; Dahlin, A.M.; Rutegård, J.; Öberg, Å.; Oldenborg, P.A.; Palmqvist, R. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS ONE 2012, 7, e47045. [Google Scholar] [CrossRef]
- Ong, S.M.; Tan, Y.C.; Beretta, O.; Jiang, D.; Yeap, W.H.; Tai, J.J.; Wong, W.C.; Yang, H.; Schwarz, H.; Lim, K.H.; et al. Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response. Eur. J. Immunol. 2012, 42, 89–100. [Google Scholar] [CrossRef]
- Larionova, I.; Tuguzbaeva, G.; Ponomaryova, A.; Stakheyeva, M.; Cherdyntseva, N.; Pavlov, V.; Choinzonov, E.; Kzhyshkowska, J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front. Oncol. 2020, 10, 566511. [Google Scholar] [CrossRef]
- Strasser, K.; Birnleitner, H.; Beer, A.; Pils, D.; Gerner, M.C.; Schmetterer, K.G.; Bachleitner-Hofmann, T.; Stift, A.; Bergmann, M.; Oehler, R. Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile. Oncoimmunology 2018, 8, e1537693. [Google Scholar] [CrossRef]
- López-Janeiro, Á.; Padilla-Ansala, C.; de Andrea, C.E.; Hardisson, D.; Melero, I. Prognostic value of macrophage polarization markers in epithelial neoplasms and melanoma. A systematic review and meta-analysis. Mod. Pathol. 2020, 33, 1458–1465. [Google Scholar] [CrossRef]
- Inagaki, K.; Kunisho, S.; Takigawa, H.; Yuge, R.; Oka, S.; Tanaka, S.; Shimamoto, F.; Chayama, K.; Kitadai, Y. Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression. Cancer Sci. 2021, 112, 2692–2704. [Google Scholar] [CrossRef]
- Kou, Y.; Li, Z.; Sun, Q.; Yang, S.; Wang, Y.; Hu, C.; Gu, H.; Wang, H.; Xu, H.; Li, Y.; et al. Prognostic value and predictive biomarkers of phenotypes of tumour-associated macrophages in colorectal cancer. Scand. J. Immunol. 2022, 95, e13137. [Google Scholar] [CrossRef]
- Konstantinov, A.S.; Kovaleva, O.V.; Samoilova, D.V.; Shelekhova, K.V. Role of macrophages in progression of colorectal cancer: A contrast with the traditional paradigm. Int. J. Clin. Exp. Pathol. 2022, 15, 403–411. [Google Scholar] [PubMed] [PubMed Central]
- Zhang, L.; Li, Z.; Skrzypczynska, K.M.; Fang, Q.; Zhang, W.; O’Brien, S.A.; He, Y.; Wang, L.; Zhang, Q.; Kim, A.; et al. Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer. Cell 2020, 181, 442–459.e29. [Google Scholar] [CrossRef] [PubMed]
- Matusiak, M.; Hickey, J.W.; van IJzendoorn, D.G.P.; Lu, G.; Kidziński, L.; Zhu, S.; Colburg, D.R.C.; Luca, B.; Phillips, D.J.; Brubaker, S.W.; et al. Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer. Cancer Discov. 2024, 14, 1418–1439. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Zhao, Y.; Gao, Y.; Li, Y.; Liu, M.; Xu, N.; Zhu, H. Age-related macrophage alterations are associated with carcinogenesis of colorectal cancer. Carcinogenesis 2022, 43, 1039–1049. [Google Scholar] [CrossRef] [PubMed]
- Cassetta, L.; Pollard, J.W. Targeting macrophages: Therapeutic approaches in cancer. Nat. Rev. Drug Discov. 2018, 17, 887–904. [Google Scholar] [CrossRef]
- Cortese, N.; Soldani, C.; Franceschini, B.; Barbagallo, M.; Marchesi, F.; Torzilli, G.; Donadon, M. Macrophages in Colorectal Cancer Liver Metastases. Cancers 2019, 11, 633. [Google Scholar] [CrossRef]
- Geng, Y.; Feng, J.; Huang, H.; Wang, Y.; Yi, X.; Wei, S.; Zhang, M.; Li, Z.; Wang, W.; Hu, W. Single-cell transcriptome analysis of tumor immune microenvironment characteristics in colorectal cancer liver metastasis. Ann. Transl. Med. 2022, 10, 1170. [Google Scholar] [CrossRef]
- Hou, S.; Zhao, Y.; Chen, J.; Lin, Y.; Qi, X. Tumor-associated macrophages in colorectal cancer metastasis: Molecular insights and translational perspectives. J. Transl. Med. 2024, 22, 62. [Google Scholar] [CrossRef]
- Sawa-Wejksza, K.; Dudek, A.; Lemieszek, M.; Kaławaj, K.; Kandefer-Szerszeń, M. Colon cancer-derived conditioned medium induces differentiation of THP-1 monocytes into a mixed population of M1/M2 cells. Tumour Biol. 2018, 40, 1010428318797880. [Google Scholar] [CrossRef]
- Frión-Herrera, Y.; Gabbia, D.; Scaffidi, M.; Zagni, L.; Cuesta-Rubio, O.; De Martin, S.; Carrara, M. Cuban Brown Propolis Interferes in the Crosstalk between Colorectal Cancer Cells and M2 Macrophages. Nutrients 2020, 12, 2040. [Google Scholar] [CrossRef]
- Xiong, K.; Deng, J.; Yue, T.; Hu, W.; Zeng, X.; Yang, T.; Xiao, T. Berberine promotes M2 macrophage polarisation through the IL-4-STAT6 signalling pathway in ulcerative colitis treatment. Heliyon 2023, 9, e14176. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Sime, W.; Juhas, M.; Sjölander, A. Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. Eur. J. Cancer 2013, 49, 3320–3334. [Google Scholar] [CrossRef] [PubMed]
- Wynn, T.A.; Chawla, A.; Pollard, J.W. Macrophage biology in development, homeostasis and disease. Nature 2013, 496, 445–455. [Google Scholar] [CrossRef] [PubMed]
- Yahaya, M.A.F.; Lila, M.A.M.; Ismail, S.; Zainol, M.; Afizan, N.A.R.N.M. Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them. J. Immunol. Res. 2019, 2019, 2368249. [Google Scholar] [CrossRef]
- Umemura, N.; Saio, M.; Suwa, T.; Kitoh, Y.; Bai, J.; Nonaka, K.; Ouyang, G.-F.; Okada, M.; Balazs, M.; Adany, R.; et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J. Leukoc. Biol. 2008, 83, 1136–1144. [Google Scholar] [CrossRef]
- Khanduri, I.; Maru, D.M.; Parra, E.R. Exploratory study of macrophage polarization and spatial distribution in colorectal cancer liver metastasis: A pilot study. Front. Immunol. 2023, 14, 1223864. [Google Scholar] [CrossRef]
- Li, Y.; Li, Q.; Yuan, R.; Wang, Y.; Guo, C.; Wang, L. Bifidobacterium breve-derived indole-3-lactic acid ameliorates colitis-associated tumorigenesis by directing the differentiation of immature colonic macrophages. Theranostics 2024, 14, 2719–2735. [Google Scholar] [CrossRef]
- Zhang, W.; Chen, L.; Ma, K.; Zhao, Y.; Liu, X.; Wang, Y.; Liu, M.; Liang, S.; Zhu, H.; Xu, N. Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells. Oncotarget 2016, 7, 75366–75378. [Google Scholar] [CrossRef]
- Hardbower, D.M.; Coburn, L.A.; Asim, M.; Singh, K.; Sierra, J.C.; Barry, D.P.; Gobert, A.P.; Piazuelo, M.B.; Washington, M.K.; Wilson, K.T. EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene 2017, 36, 3807–3819. [Google Scholar] [CrossRef]
- Deng, Y.M.; Zhao, C.; Wu, L.; Qu, Z.; Wang, X.Y. Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR. Cell Death Discov. 2022, 8, 273. [Google Scholar] [CrossRef]
- Wang, L.; Li, S.; Luo, H.; Lu, Q.; Yu, S. PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J. Exp. Clin. Cancer Res. 2022, 41, 303. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Xu, Y.; Zhong, J.; Wang, H.; Weng, M.; Cheng, Q.; Wu, Q.; Sun, Z.; Jiang, H.; Zhu, M.; et al. MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway. Oncotarget 2016, 7, 78726–78735. [Google Scholar] [CrossRef] [PubMed]
- Zhong, Q.; Fang, Y.; Lai, Q.; Wang, S.; He, C.; Li, A.; Liu, S.; Yan, Q. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling. J. Exp. Clin. Cancer Res. 2020, 39, 132. [Google Scholar] [CrossRef]
- Fu, Y.; Zhang, X.; Qiao, Q. PLXDC1 serves as a potential prognostic marker and involves in malignant progression and macrophage polarization in colon cancer. J. Biochem. Mol Toxicol. 2024, 38, e23832. [Google Scholar] [CrossRef]
- Wang, X.; Wang, J.; Zhao, J.; Wang, H.; Chen, J.; Wu, J. HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment. Theranostics 2022, 12, 963–975. [Google Scholar] [CrossRef]
- Li, R.; Zhou, R.; Wang, H.; Li, W.; Pan, M.; Yao, X.; Zhan, W.; Yang, S.; Xu, L.; Ding, Y.; et al. Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer. Cell Death Differ. 2019, 26, 2447–2463. [Google Scholar] [CrossRef]
- Cao, Y.; Wo, M.; Xu, C.; Fei, X.; Jin, J.; Shan, Z. An AMPK agonist suppresses the progress of colorectal cancer by regulating the polarization of TAM to M1 through inhibition of HIF-1α and mTOR signal pathway. J. Cancer Res. Ther. 2023, 19, 1560–1567. [Google Scholar] [CrossRef]
- Lai, X.; Liu, B.; Wan, Y.; Zhou, P.; Li, W.; Hu, W.; Gong, W. Metformin alleviates colitis-associated colorectal cancer via inhibition of the TLR4/MyD88/NFκB/MAPK pathway and macrophage M2 polarization. Int. Immunopharmacol. 2025, 144, 113683. [Google Scholar] [CrossRef]
- Cheng, Y.; Zhu, Y.; Xu, J.; Yang, M.; Chen, P.; Xu, W.; Zhao, J.; Geng, L.; Gong, S. PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway. Mol. Cancer 2018, 17, 13. [Google Scholar] [CrossRef]
- Popēna, I.; Ābols, A.; Saulīte, L.; Pleiko, K.; Zandberga, E.; Jēkabsons, K.; Endzeliņš, E.; Llorente, A.; Linē, A.; Riekstiņa, U. Effect of colorectal cancer-derived extracellular vesicles on the immunophenotype and cytokine secretion profile of monocytes and macrophages. Cell Commun. Signal. 2018, 16, 17. [Google Scholar] [CrossRef]
- de Carvalho, T.G.; Lara, P.; Jorquera-Cordero, C.; Aragão, C.F.S.; Oliveira, A.d.S.; Garcia, V.B.; Souza, S.V.d.P.; Schomann, T.; Soares, L.A.L.; Guedes, P.M.d.M.; et al. Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea. Biomed. Pharmacother. 2023, 168, 115663. [Google Scholar] [CrossRef] [PubMed]
- De Vito, A.; Orecchia, P.; Balza, E.; Reverberi, D.; Scaldaferri, D.; Taramelli, R.; Noonan, D.M.; Acquati, F.; Mortara, L. Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection. Cancers 2020, 12, 717. [Google Scholar] [CrossRef] [PubMed]
- Tu, W.; Gong, J.; Zhou, Z.; Tian, D.; Wang, Z. TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. Cell Death Dis. 2021, 12, 882. [Google Scholar] [CrossRef]
- Rajtmajerová, M.; Trailin, A.; Liška, V.; Hemminki, K.; Ambrozkiewicz, F. Long Non-Coding RNA and microRNA Interplay in Colorectal Cancer and Their Effect on the Tumor Microenvironment. Cancers 2022, 14, 5450. [Google Scholar] [CrossRef]
- Zhang, J.; Li, K.; Zheng, H.; Zhu, Y. Research progress review on long non-coding RNA in colorectal cancer. Neoplasma 2021, 68, 240–252. [Google Scholar] [CrossRef]
- Lulli, M.; Napoli, C.; Landini, I.; Mini, E.; Lapucci, A. Role of Non-Coding RNAs in Colorectal Cancer: Focus on Long Non-Coding RNAs. Int. J. Mol. Sci. 2022, 23, 13431. [Google Scholar] [CrossRef]
- Farzam, O.R.; Eslami, S.; Jafarizadeh, A.; Alamdari, S.G.; Dabbaghipour, R.; Nobari, S.A.; Baradaran, B. The significance of exosomal non-coding RNAs (ncRNAs) in the metastasis of colorectal cancer and development of therapy resistance. Gene 2025, 937, 149141. [Google Scholar] [CrossRef]
- Liang, Z.; Liu, H.; Wang, F.; Xiong, L.; Zhou, C.; Hu, T.; He, X.-W.; Wu, X.-J.; Xie, D.; Wu, X.-R.; et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis. 2019, 10, 829, Erratum in: Cell Death Dis. 2020, 11, 465. [Google Scholar] [CrossRef]
- Xu, J.; Liu, X.Y.; Zhang, Q.; Liu, H.; Zhang, P.; Tian, Z.B.; Zhang, C.P.; Li, X.Y. Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development. Front. Oncol. 2022, 11, 810893. [Google Scholar] [CrossRef]
- St Laurent, G.; Wahlestedt, C.; Kapranov, P. The Landscape of long noncoding RNA classification. Trends Genet. 2015, 31, 239–251. [Google Scholar] [CrossRef]
- Hombach, S.; Kretz, M. Non-Coding RNAs: Classification, Biology and Functioning. Adv. Exp. Med. Biol. 2016, 937, 3–17. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Lan, Q.; Lai, W.; Wu, H.; Xu, H.; Fang, K.; Chu, Z.; Zeng, Y. Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p. BMC Cancer 2022, 22, 928. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Tang, S.; Gao, Y.; Lu, Z.; Yang, Y.; Chen, J.; Li, T. Application of exosomal miRNA mediated macrophage polarization in colorectal cancer: Current progress and challenges. Oncol. Res. 2023, 32, 61–71. [Google Scholar] [CrossRef]
- Gao, B.; Wang, L.; Wen, T.; Xie, X.; Rui, X.; Chen, Q. Colon Cancer-Derived Exosomal LncRNA-XIST Promotes M2-like Macrophage Polarization by Regulating PDGFRA. Int. J. Mol. Sci. 2024, 25, 11433. [Google Scholar] [CrossRef]
- Liu, Y.; Lv, H.; Liu, X.; Xu, L.; Li, T.; Zhou, H.; Zhu, H.; Hao, C.; Lin, C.; Zhang, Y. The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization. J. Exp. Clin. Cancer Res. 2024, 43, 195. [Google Scholar] [CrossRef]
- Ding, A.X.; Wang, H.; Zhang, J.M.; Yang, W.; Kuang, Y.T. lncRNA BANCR promotes the colorectal cancer metastasis through accelerating exosomes-mediated M2 macrophage polarization via regulating RhoA/ROCK signaling. Mol. Cell. Biochem. 2024, 479, 13–27. [Google Scholar] [CrossRef]
- Liang, Y.; Li, J.; Yuan, Y.; Ju, H.; Liao, H.; Li, M.; Liu, Y.; Yao, Y.; Yang, L.; Li, T.; et al. Exosomal miR-106a-5p from highly metastatic colorectal cancer cells drives liver metastasis by inducing macrophage M2 polarization in the tumor microenvironment. J. Exp. Clin. Cancer Res. 2024, 43, 281. [Google Scholar] [CrossRef]
- Wang, Y.; Yu, G.; Liu, Y.; Xie, L.; Ge, J.; Zhao, G.; Lin, J. Hypoxia-induced PTTG3P contributes to colorectal cancer glycolysis and M2 phenotype of macrophage. Biosci. Rep. 2021, 41, BSR20210764. [Google Scholar] [CrossRef]
- Zhang, J.; Li, S.; Zhang, X.; Li, C.; Zhang, J.; Zhou, W. LncRNA HLA-F-AS1 promotes colorectal cancer metastasis by inducing PFN1 in colorectal cancer-derived extracellular vesicles and mediating macrophage polarization. Cancer Gene Ther. 2021, 28, 1269–1284. [Google Scholar] [CrossRef]
- Zhou, L.; Li, J.; Liao, M.; Zhang, Q.; Yang, M. LncRNA MIR155HG induces M2 macrophage polarization and drug resistance of colorectal cancer cells by regulating ANXA2. Cancer Immunol. Immunother. 2022, 71, 1075–1091. [Google Scholar] [CrossRef]
- Gao, C.; Hu, W.; Zhao, J.; Ni, X.; Xu, Y. LncRNA HCG18 promotes M2 macrophage polarization to accelerate cetuximab resistance in colorectal cancer through regulating miR-365a-3p/FOXO1/CSF-1 axis. Pathol. Res. Pract. 2022, 240, 154227. [Google Scholar] [CrossRef] [PubMed]
- Zheng, J.; Dou, R.; Zhang, X.; Zhong, B.; Fang, C.; Xu, Q.; Di, Z.; Huang, S.; Lin, Z.; Song, J.; et al. LINC00543 promotes colorectal cancer metastasis by driving EMT and inducing the M2 polarization of tumor associated macrophages. J. Transl. Med. 2023, 21, 153. [Google Scholar] [CrossRef] [PubMed]
- Yin, Y.; Liu, B.; Cao, Y.; Yao, S.; Liu, Y.; Jin, G.; Qin, Y.; Chen, Y.; Cui, K.; Zhou, L.; et al. Colorectal Cancer-Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating PD-L1 Expression in Tumor-Associated Macrophages. Adv. Sci. 2022, 9, 2102620. [Google Scholar] [CrossRef]
- Dai, S.; Zhuang, H.; Li, Z.; Chen, Z.; Chai, Y.; Zhou, Q. miR-122/NEGR1 axis contributes colorectal cancer liver metastasis by PI3K/AKT pathway and macrophage modulation. J. Transl. Med. 2024, 22, 1060. [Google Scholar] [CrossRef]
- Zhou, J.; Song, Q.; Li, H.; Han, Y.; Pu, Y.; Li, L.; Rong, W.; Liu, X.; Wang, Z.; Sun, J.; et al. Targeting circ-0034880-enriched tumor extracellular vesicles to impede SPP1highCD206+ pro-tumor macrophages mediated pre-metastatic niche formation in colorectal cancer liver metastasis. Mol. Cancer 2024, 23, 168. [Google Scholar] [CrossRef]
- Lai, F.; Zhang, H.; Xu, B.; Xie, Y.; Yu, H. Long non-coding RNA NBR2 suppresses the progress of colorectal cancer in vitro and in vivo by regulating the polarization of TAM. Bioengineered 2021, 12, 5462–5475. [Google Scholar] [CrossRef]
- Yang, X.; Luo, Y.; Li, M.; Jin, Z.; Chen, G.; Gan, C. Long non-coding RNA NBR2 suppresses the progression of colorectal cancer by downregulating miR-19a to regulate M2 macrophage polarization. Chin. J. Physiol. 2023, 66, 546–557. [Google Scholar] [CrossRef]
- Zou, J.; Wu, B.; Lin, C.; Ding, Q.; Li, J. MiR-216b targets CPEB4 to suppress colorectal cancer progression through inhibiting IL-10-mediated M2 polarization of tumor-associated macrophages. Am. J. Transl. Res. 2022, 14, 8129–8145. [Google Scholar] [PubMed] [PubMed Central]
- Chen, C.; Huang, Z.; Tan, X.; Wang, R.; Liu, J.; Zhang, M. The microRNA-4766/VEGFA axis mediates macrophage M2-type polarization to inhibit colorectal cancer proliferation and migration. Pathol. Res. Pract. 2023, 250, 154767. [Google Scholar] [CrossRef]
- Ma, D.; Zhang, Y.; Chen, G.; Yan, J. miR-148a Affects Polarization of THP-1-Derived Macrophages and Reduces Recruitment of Tumor-Associated Macrophages via Targeting SIRPα. Cancer Manag. Res. 2020, 12, 8067–8077. [Google Scholar] [CrossRef]
- Chen, J.; Li, Z.; Yue, C.; Ma, J.; Cao, L.; Lin, J.; Zhu, D.; An, R.; Lai, J.; Guo, Y.; et al. Human umbilical cord mesenchymal stem cell-derived exosomes carrying miR-1827 downregulate SUCNR1 to inhibit macrophage M2 polarization and prevent colorectal liver metastasis. Apoptosis 2023, 28, 549–565. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.; Mu, J.; Hu, X.; Samykutty, A.; Zhuang, X.; Deng, Z.; Zhang, L.; Cao, P.; Yan, J.; Miller, D.; et al. Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages. Oncotarget 2016, 7, 25683–25697. [Google Scholar] [CrossRef] [PubMed]
- Zhou, S.; Zhu, C.; Jin, S.; Cui, C.; Xiao, L.; Yang, Z.; Wang, X.; Yu, J. The intestinal microbiota influences the microenvironment of metastatic colon cancer by targeting miRNAs. FEMS Microbiol. Lett. 2022, 369, fnac023. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Li, L.; Xu, C.; Wang, Y.; Wang, Z.; Chen, M.; Jiang, Z.; Pan, J.; Yang, C.; Li, X.; et al. Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis. Gut. 2020, 70, 1495–1506. [Google Scholar] [CrossRef]
- Fan, L.; Xu, C.; Ge, Q.; Lin, Y.; Wong, C.C.; Qi, Y.; Ye, B.; Lian, Q.; Zhuo, W.; Si, J.; et al. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs. Cancer Immunol. Res. 2021, 9, 1111–1124. [Google Scholar] [CrossRef]
- Xu, C.; Fan, L.; Lin, Y.; Shen, W.; Qi, Y.; Zhang, Y.; Chen, Z.; Wang, L.; Long, Y.; Hou, T.; et al. Fusobacterium nucleatum promotes colorectal cancer metastasis through miR-1322/CCL20 axis and M2 polarization. Gut Microbes 2021, 13, 1980347. [Google Scholar] [CrossRef]
- Hu, L.; Liu, Y.; Kong, X.; Wu, R.; Peng, Q.; Zhang, Y.; Zhou, L.; Duan, L. Fusobacterium nucleatum Facilitates M2 Macrophage Polarization and Colorectal Carcinoma Progression by Activating TLR4/NF-κB/S100A9 Cascade. Front. Immunol. 2021, 12, 658681. [Google Scholar] [CrossRef]
- Gu, J.; Sun, R.; Tang, D.; Liu, F.; Chang, X.; Wang, Q. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. suppresses growth and metastasis of colorectal cancer cells by inhibiting M2 macrophage polarization via a Sp1/ZFAS1/miR-153-3p/CCR5 regulatory axis. Cell Biol. Toxicol. 2022, 38, 679–697. [Google Scholar] [CrossRef]
- Faghfuri, E.; Gholizadeh, P. The role of Akkermansia muciniphila in colorectal cancer: A double-edged sword of treatment or disease progression? Biomed. Pharmacother 2024, 173, 116416. [Google Scholar] [CrossRef]
- Wu, J.; Li, K.; Peng, W.; Li, H.; Li, Q.; Wang, X.; Peng, Y.; Tang, X.; Fu, X. Autoinducer-2 of Fusobacterium nucleatum promotes macrophage M1 polarization via TNFSF9/IL-1β signaling. Int. Immunopharmacol. 2019, 74, 105724. [Google Scholar] [CrossRef]
- Li, Q.; Peng, W.; Wu, J.; Wang, X.; Ren, Y.; Li, H.; Peng, Y.; Tang, X.; Fu, X. Autoinducer-2 of gut microbiota, a potential novel marker for human colorectal cancer, is associated with the activation of TNFSF9 signaling in macrophages. Oncoimmunology 2019, 8, e1626192. [Google Scholar] [CrossRef] [PubMed]
- Gu, J.; Xu, X.; Li, X.; Yue, L.; Zhu, X.; Chen, Q.; Gao, J.; Takashi, M.; Zhao, W.; Zhao, B.; et al. Tumor-resident microbiota contributes to colorectal cancer liver metastasis by lactylation and immune modulation. Oncogene 2024, 43, 2389–2404. [Google Scholar] [CrossRef] [PubMed]
- Sadeghi, M.; Amari, A.; Asadirad, A.; Nemati, M.; Khodadadi, A. F1 fraction isolated from Mesobuthus eupeus scorpion venom induces macrophage polarization toward M1 phenotype and exerts anti-tumoral effects on the CT26 tumor cell line. Int. Immunopharmacol. 2024, 132, 111960. [Google Scholar] [CrossRef] [PubMed]
- Srairi-Abid, N.; Othman, H.; Aissaoui, D.; BenAissa, R. Anti-tumoral effect of scorpion peptides: Emerging new cellular targets and signaling pathways. Cell Calcium 2019, 80, 160–174. [Google Scholar] [CrossRef]
- Valizade, M.; Raesi Vanani, A.; Rezaei, M.; Khorsandi, L.S.; Zeidooni, L.; Mahdavinia, M. Mesobuthus eupeus venom induced injury in the colorectal carcinoma cell line (HT29) through altering the mitochondria membrane stability. Iran. J. Basic Med. Sci. 2020, 23, 760–767. [Google Scholar] [CrossRef]
- Ling, Q.; Fang, J.; Zhai, C.; Huang, W.; Chen, Y.; Zhou, T.; Liu, Y.; Fang, X. Berberine induces SOCS1 pathway to reprogram the M1 polarization of macrophages via miR-155-5p in colitis-associated colorectal cancer. Eur. J. Pharmacol. 2023, 949, 175724, Erratum in: Eur. J. Pharmacol. 2023, 959, 176109. [Google Scholar] [CrossRef]
- Jumaniyazova, E.; Lokhonina, A.; Dzhalilova, D.; Miroshnichenko, E.; Kosyreva, A.; Fatkhudinov, T. The Role of Macrophages in Various Types of Tumors and the Possibility of Their Use as Targets for Anti-Tumor Therapy. Cancers 2025, 17, 342. [Google Scholar] [CrossRef]
- Li, S.; Xu, F.; Zhang, J.; Wang, L.; Zheng, Y.; Wu, X.; Wang, J.; Huang, Q.; Lai, M. Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. Oncoimmunology 2017, 7, e1380765. [Google Scholar] [CrossRef]
- Väyrynen, J.P.; Haruki, K.; Lau, M.C.; Väyrynen, S.A.; Zhong, R.; Dias Costa, A.; Borowsky, J.; Zhao, M.; Fujiyoshi, K.; Arima, K.; et al. The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment. Cancer Immunol. Res. 2021, 9, 8–19. [Google Scholar] [CrossRef]
- Wang, X.; Yuwen, T.J.; Zhong, Y.; Li, Z.G.; Wang, X.Y. A new method for predicting the prognosis of colorectal cancer patients through a combination of multiple tumor-associated macrophage markers at the invasive front. Heliyon 2023, 9, e13211. [Google Scholar] [CrossRef]
- Coletta, S.; Lonardi, S.; Sensi, F.; D’angelo, E.; Fassan, M.; Pucciarelli, S.; Valzelli, A.; Biccari, A.; Vermi, W.; Della Bella, C.; et al. Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC. Cancers 2021, 13, 5199. [Google Scholar] [CrossRef] [PubMed]
- Mola, S.; Pandolfo, C.; Sica, A.; Porta, C. The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance. Int. J. Mol. Sci. 2020, 21, 6866. [Google Scholar] [CrossRef] [PubMed]
- Gulubova, M.; Ananiev, J.; Yovchev, Y.; Julianov, A.; Karashmalakov, A.; Vlaykova, T. The density of macrophages in colorectal cancer is inversely correlated to TGF-β1 expression and patients’ survival. J. Mol. Histol. 2013, 44, 679–692. [Google Scholar] [CrossRef] [PubMed]
- Waniczek, D.; Lorenc, Z.; Śnietura, M.; Wesecki, M.; Kopec, A.; Muc-Wierzgoń, M. Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the Clinical Outcome in Colorectal Cancer. Arch. Immunol. Ther. Exp. 2017, 65, 445–454. [Google Scholar] [CrossRef]
- Koelzer, V.H.; Canonica, K.; Dawson, H.; Sokol, L.; Karamitopoulou-Diamantis, E.; Lugli, A.; Zlobec, I. Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology 2015, 5, e1106677. [Google Scholar] [CrossRef]
- Pinto, M.L.; Rios, E.; Durães, C.; Ribeiro, R.; Machado, J.C.; Mantovani, A.; Barbosa, M.A.; Carneiro, F.; Oliveira, M.J. The Two Faces of Tumor-Associated Macrophages and Their Clinical Significance in Colorectal Cancer. Front. Immunol. 2019, 10, 1875. [Google Scholar] [CrossRef]
- Majid, U.; Bergsland, C.H.; Sveen, A.; Bruun, J.; Eilertsen, I.A.; Bækkevold, E.S.; Nesbakken, A.; Yaqub, S.; Jahnsen, F.L.; Lothe, R.A. The prognostic effect of tumor-associated macrophages in stage I-III colorectal cancer depends on T cell infiltration. Cell. Oncol. 2024, 47, 1267–1276. [Google Scholar] [CrossRef]
- Algars, A.; Irjala, H.; Vaittinen, S.; Huhtinen, H.; Sundström, J.; Salmi, M.; Ristamäki, R.; Jalkanen, S. Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int. J. Cancer 2012, 131, 864–873. [Google Scholar] [CrossRef]
- Ding, D.; Yao, Y.; Yang, C.; Zhang, S. Identification of mannose receptor and CD163 as novel biomarkers for colorectal cancer. Cancer Biomark. 2018, 21, 689–700. [Google Scholar] [CrossRef]
- Wei, C.; Yang, C.; Wang, S.; Shi, D.; Zhang, C.; Lin, X.; Liu, Q.; Dou, R.; Xiong, B. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol. Cancer 2019, 18, 64. [Google Scholar] [CrossRef]
- Yang, C.; Wei, C.; Wang, S.; Shi, D.; Zhang, C.; Lin, X.; Dou, R.; Xiong, B. Elevated CD163+/CD68+ Ratio at Tumor Invasive Front is Closely Associated with Aggressive Phenotype and Poor Prognosis in Colorectal Cancer. Int. J. Biol. Sci. 2019, 15, 984–998. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.W.; Liu, L.; Gong, C.Y.; Shi, H.S.; Zeng, Y.H.; Wang, X.Z.; Zhao, Y.W.; Wei, Y.Q. Prognostic significance of tumor-associated macrophages in solid tumor: A meta-analysis of the literature. PLoS ONE 2012, 7, e50946. [Google Scholar] [CrossRef] [PubMed]
- Feng, Q.; Chang, W.; Mao, Y.; He, G.; Zheng, P.; Tang, W.; Wei, Y.; Ren, L.; Zhu, D.; Ji, M.; et al. Tumor-Associated Macrophages as Prognostic and Predictive Biomarkers for Postoperative Adjuvant Chemotherapy in Patients with Stage II Colon Cancer. Clin. Cancer Res. 2019, 25, 3896–3907. [Google Scholar] [CrossRef]
- Kielbassa, K.; Vegna, S.; Ramirez, C.; Akkari, L. Understanding the Origin and Diversity of Macrophages to Tailor Their Targeting in Solid Cancers. Front. Immunol. 2019, 10, 2215. [Google Scholar] [CrossRef]
- Yang, H.; Shao, R.; Huang, H.; Wang, X.; Rong, Z.; Lin, Y. Engineering macrophages to phagocytose cancer cells by blocking the CD47/SIRPɑ axis. Cancer Med. 2019, 8, 4245–4253. [Google Scholar] [CrossRef]
- Chen, Y.; Jin, H.; Song, Y.; Huang, T.; Cao, J.; Tang, Q.; Zou, Z. Targeting tumor-associated macrophages: A potential treatment for solid tumors. J. Cell. Physiol. 2021, 236, 3445–3465. [Google Scholar] [CrossRef]
- Cheruku, S.; Rao, V.; Pandey, R.; Rao Chamallamudi, M.; Velayutham, R.; Kumar, N. Tumor-associated macrophages employ immunoediting mechanisms in colorectal tumor progression: Current research in Macrophage repolarization immunotherapy. Int. Immunopharmacol. 2023, 116, 109569. [Google Scholar] [CrossRef]
- Liu, Z.; Xie, Y.; Xiong, Y.; Liu, S.; Qiu, C.; Zhu, Z.; Mao, H.; Yu, M.; Wang, X. TLR 7/8 agonist reverses oxaliplatin resistance in colorectal cancer via directing the myeloid-derived suppressor cells to tumoricidal M1-macrophages. Cancer Lett. 2020, 469, 173–185. [Google Scholar] [CrossRef]
- Sanchez-Lopez, E.; Flashner-Abramson, E.; Shalapour, S.; Zhong, Z.; Taniguchi, K.; Levitzki, A.; Karin, M. Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Oncogene 2016, 35, 2634–2644. [Google Scholar] [CrossRef]
- Lee, K.-H.; Yen, W.-C.; Lin, W.-H.; Wang, P.-C.; Lai, Y.-L.; Su, Y.-C.; Chang, C.-Y.; Wu, C.-S.; Huang, Y.-C.; Yang, C.-M.; et al. Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Anti-tumor and Immunomodulatory Activity in a Murine Colon Tumor Model. J. Med. Chem. 2021, 64, 14477–14497. [Google Scholar] [CrossRef]
- Lv, Q.; Pan, X.; Wang, D.; Rong, Q.; Ma, B.; Xie, X.; Zhang, Y.; Wang, J.; Hu, L. Discovery of (Z)-1-(3-((1H-Pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea Derivatives as Novel and Orally Highly Effective CSF-1R Inhibitors for Potential Colorectal Cancer Immunotherapy. J. Med. Chem. 2021, 64, 17184–17208. [Google Scholar] [CrossRef] [PubMed]
- Fang, Y.; He, Y.; Wu, C.; Zhang, M.; Gu, Z.; Zhang, J.; Liu, E.; Xu, Q.; Asrorov, A.M.; Huang, Y. Magnetism-mediated targeting hyperthermia-immunotherapy in "cold" tumor with CSF1R inhibitor. Theranostics 2021, 11, 6860–6872. [Google Scholar] [CrossRef] [PubMed]
- Kateh Shamshiri, M.; Jaafari, M.R.; Badiee, A. Preparation of liposomes containing IFN-gamma and their potentials in cancer immunotherapy: In vitro and in vivo studies in a colon cancer mouse model. Life Sci. 2021, 264, 118605. [Google Scholar] [CrossRef] [PubMed]
- Kauder, S.E.; Kuo, T.C.; Harrabi, O.; Chen, A.; Sangalang, E.; Doyle, L.; Rocha, S.S.; Bollini, S.; Han, B.; Sim, J.; et al. ALX148 blocks CD47 and enhances innate and adaptive anti-tumor immunity with a favorable safety profile. PLoS ONE 2018, 13, e0201832. [Google Scholar] [CrossRef]
- Kuo, T.C.; Chen, A.; Harrabi, O.; Sockolosky, J.T.; Zhang, A.; Sangalang, E.; Doyle, L.V.; Kauder, S.E.; Fontaine, D.; Bollini, S.; et al. Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity. J. Hematol. Oncol. 2020, 13, 160. [Google Scholar] [CrossRef]
- Andrejeva, G.; Capoccia, B.J.; Hiebsch, R.R.; Donio, M.J.; Darwech, I.M.; Puro, R.J.; Pereira, D.S. Novel SIRPα Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells. J. Immunol. 2021, 206, 712–721. [Google Scholar] [CrossRef]
- Mantovani, A.; Allavena, P.; Marchesi, F.; Garlanda, C. Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug Discov. 2022, 21, 799–820. [Google Scholar] [CrossRef]
- Haag, G.M.; Springfeld, C.; Grün, B.; Apostolidis, L.; Zschäbitz, S.; Dietrich, M.; Berger, A.-K.; Weber, T.F.; Zoernig, I.; Schaaf, M.; et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer—The PICCASSO phase I trial. Eur. J. Cancer 2022, 167, 112–122. [Google Scholar] [CrossRef]
- Georgoudaki, A.M.; Prokopec, K.E.; Boura, V.F.; Hellqvist, E.; Sohn, S.; Östling, J.; Dahan, R.; Harris, R.A.; Rantalainen, M.; Klevebring, D.; et al. Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis. Cell Rep. 2016, 15, 2000–2011. [Google Scholar] [CrossRef]
- Olsson, A.; Nakhlé, J.; Sundstedt, A.; Plas, P.; Bauchet, A.-L.; Pierron, V.; Bruetschy, L.; Deronic, A.; Törngren, M.; Liberg, D.; et al. Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment. J. Immunother. Cancer 2015, 3, 53. [Google Scholar] [CrossRef]
- Li, C.; Song, J.; Guo, Z.; Gong, Y.; Zhang, T.; Huang, J.; Cheng, R.; Yu, X.; Li, Y.; Chen, L.; et al. EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment. Front. Immunol. 2022, 13, 857808. [Google Scholar] [CrossRef] [PubMed]
- Zhu, M.; Bai, L.; Liu, X.; Peng, S.; Xie, Y.; Bai, H.; Yu, H.; Wang, X.; Yuan, P.; Ma, R.; et al. Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages. J. Immunother. Cancer 2022, 10, e005610. [Google Scholar] [CrossRef] [PubMed]
- Limagne, E.; Thibaudin, M.; Nuttin, L.; Spill, A.; Derangère, V.; Fumet, J.D.; Amellal, N.; Peranzoni, E.; Cattan, V.; Ghiringhelli, F. Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 Blockade in Colorectal Cancer by Inducing Immunogenic Cell Death and Depleting Macrophages. Cancer Immunol. Res. 2019, 7, 1958–1969. [Google Scholar] [CrossRef]
- Cieslewicz, M.; Tang, J.; Yu, J.L.; Cao, H.; Zavaljevski, M.; Motoyama, K.; Lieber, A.; Raines, E.W.; Pun, S.H. Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. Proc. Natl. Acad. Sci. USA 2013, 110, 15919–15924. [Google Scholar] [CrossRef]
- Ries, C.H.; Cannarile, M.A.; Hoves, S.; Benz, J.; Wartha, K.; Runza, V.; Rey-Giraud, F.; Pradel, L.P.; Feuerhake, F.; Klaman, I.; et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014, 25, 846–859. [Google Scholar] [CrossRef]
- Kato, Y.; Tabata, K.; Kimura, T.; Yachie-Kinoshita, A.; Ozawa, Y.; Yamada, K.; Ito, J.; Tachino, S.; Hori, Y.; Matsuki, M.; et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE 2019, 14, e0212513. [Google Scholar] [CrossRef]
- Papadopoulos, K.P.; Gluck, L.; Martin, L.P.; Olszanski, A.J.; Tolcher, A.W.; Ngarmchamnanrith, G.; Rasmussen, E.; Amore, B.M.; Nagorsen, D.; Hill, J.S.; et al. First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2017, 23, 5703–5710. [Google Scholar] [CrossRef]
- Razak, A.R.; Cleary, J.M.; Moreno, V.; Boyer, M.; Aller, E.C.; Edenfield, W.; Tie, J.; Harvey, R.D.; Rutten, A.; A Shah, M.; et al. Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. J. Immunother. Cancer 2020, 8, e001006. [Google Scholar] [CrossRef]
- Shi, G.; Yang, Q.; Zhang, Y.; Jiang, Q.; Lin, Y.; Yang, S.; Wang, H.; Cheng, L.; Zhang, X.; Li, Y.; et al. Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy. Mol. Ther. 2019, 27, 244–260. [Google Scholar] [CrossRef]
- Zhao, Y.; Liu, X.; Huo, M.; Wang, Y.; Li, Y.; Xu, N.; Zhu, H. Cetuximab enhances the anti-tumor function of macrophages in an IL-6 dependent manner. Life Sci. 2021, 267, 118953. [Google Scholar] [CrossRef]
- Suarez-Carmona, M.; Chaorentong, P.; Kather, J.N.; Rothenheber, R.; Ahmed, A.; Berthel, A.; Heinzelmann, A.; Moraleda, R.; Valous, N.A.; Kosaloglu, Z.; et al. CCR5 status and metastatic progression in colorectal cancer. Oncoimmunology 2019, 8, e1626193. [Google Scholar] [CrossRef] [PubMed]
- Doleschel, D.; Hoff, S.; Koletnik, S.; Rix, A.; Zopf, D.; Kiessling, F.; Lederle, W. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. J. Exp. Clin. Cancer Res. 2021, 40, 288. [Google Scholar] [CrossRef] [PubMed]
- Halama, N.; Zoernig, I.; Berthel, A.; Kahlert, C.; Klupp, F.; Suarez-Carmona, M.; Suetterlin, T.; Brand, K.; Krauss, J.; Lasitschka, F.; et al. Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell 2016, 29, 587–601. [Google Scholar] [CrossRef]
- Krulich, L.; Dhariwal, A.P.; McCann, S.M. Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 1968, 83, 783–790. [Google Scholar] [CrossRef]
- Brazeau, P.; Vale, W.; Burgus, R.; Ling, N.; Butcher, M.; Rivier, J.; Guillemin, R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973, 179, 77–79. [Google Scholar] [CrossRef]
- Kumar, U. Somatostatin and Somatostatin Receptors in Tumour Biology. Int. J. Mol. Sci. 2023, 25, 436. [Google Scholar] [CrossRef]
- Weinstock, J.V.; Blum, A.M.; Malloy, T. Macrophages within the granulomas of murine Schistosoma mansoni are a source of a somatostatin 1-14-like molecule. Cell. Immunol. 1990, 131, 381–390. [Google Scholar] [CrossRef]
- Elliott, D.E.; Blum, A.M.; Li, J.; Metwali, A.; Weinstock, J.V. Preprosomatostatin messenger RNA is expressed by inflammatory cells and induced by inflammatory mediators and cytokines. J. Immunol. 1998, 160, 3997–4003. [Google Scholar] [CrossRef] [PubMed]
- Reubi, J.C.; Horisberger, U.; Kappeler, A.; Laissue, J.A. Localization of receptors for vasoactive intestinal peptide, somatostatin, and substance P in distinct compartments of human lymphoid organs. Blood 1998, 92, 191–197. [Google Scholar] [CrossRef] [PubMed]
- Zavros, Y.; Kao, J.Y.; Merchant, J.L. Inflammation and cancer III. Somatostatin and the innate immune system. Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286, G698–G701. [Google Scholar] [CrossRef]
- Silva, A.B.; Palmer, D.B. Evidence of conserved neuroendocrine interactions in the thymus: Intrathymic expression of neuropeptides in mammalian and non-mammalian vertebrates. Neuroimmunomodulation 2011, 18, 264–270. [Google Scholar] [CrossRef] [PubMed]
- Artem’eva, I.L.; Sergeeva, V.E.; Smorodchenko, A.T. Thymic Structures Containing Somatostatin. Bull. Exp. Biol. Med. 2015, 159, 387–389. [Google Scholar] [CrossRef] [PubMed]
- Gao, R.; Yang, T.; Zhang, Q. δ-Cells: The Neighborhood Watch in the Islet Community. Biology 2021, 10, 74. [Google Scholar] [CrossRef]
- Shamsi, B.H.; Chatoo, M.; Xu, X.K.; Xu, X.; Chen, X.Q. Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System. Front. Endocrinol. 2021, 12, 652363. [Google Scholar] [CrossRef]
- Weinstock, J.V.; Elliott, D. The somatostatin immunoregulatory circuit present at sites of chronic inflammation. Eur. J. Endocrinol. 2000, 143 (Suppl. S1), S15–S19. [Google Scholar] [CrossRef]
- El-Salhy, M.; Solomon, T.; Hausken, T.; Gilja, O.H.; Hatlebakk, J.G. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J. Gastroenterol. 2017, 23, 5068–5085. [Google Scholar] [CrossRef]
- Gonkowski, S.; Rytel, L. Somatostatin as an Active Substance in the Mammalian Enteric Nervous System. Int. J. Mol. Sci. 2019, 20, 4461. [Google Scholar] [CrossRef]
- Zavros, Y.; Rathinavelu, S.; Kao, J.Y.; Todisco, A.; Del Valle, J.; Weinstock, J.V.; Low, M.J.; Merchant, J.L. Treatment of Helicobacter gastritis with IL-4 requires somatostatin. Proc. Natl. Acad. Sci. USA 2003, 100, 12944–12949. [Google Scholar] [CrossRef]
- Kao, J.Y.; Pierzchala, A.; Rathinavelu, S.; Zavros, Y.; Tessier, A.; Merchant, J.L. Somatostatin inhibits dendritic cell responsiveness to Helicobacter pylori. Regul. Pept. 2006, 134, 23–29. [Google Scholar] [CrossRef]
- Perez, J.; Viollet, C.; Doublier, S.; Videau, C.; Epelbaum, J.; Baud, L. Somatostatin binds to murine macrophages through two distinct subsets of receptors. J. Neuroimmunol. 2003, 138, 38–44. [Google Scholar] [CrossRef]
- Elliott, D.E.; Li, J.; Blum, A.M.; Metwali, A.; Patel, Y.C.; Weinstock, J.V. SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-gamma release. Eur. J. Immunol. 1999, 29, 2454–2463. [Google Scholar] [CrossRef]
- Peck, R. Neuropeptides modulating macrophage function. Ann. N. Y. Acad. Sci. 1987, 496, 264–270. [Google Scholar] [CrossRef] [PubMed]
- Ferone, D.; Pivonello, R.; Van Hagen, P.M.; Waaijers, M.; Zuijderwijk, J.; Colao, A.; Lombardi, G.; Bogers, A.J.; Lamberts, S.W.; Hofland, L.J. Age-related decrease of somatostatin receptor number in the normal human thymus. Am. J. Physiol. Endocrinol. Metab. 2000, 279, E791–E798. [Google Scholar] [CrossRef] [PubMed]
- Gomariz, R.P.; Lorenzo, M.J.; Cacicedo, L.; Vicente, A.; Zapata, A.G. Demonstration of immunoreactive vasoactive intestinal peptide (IR-VIP) and somatostatin (IR-SOM) in rat thymus. Brain Behav. Immun. 1990, 4, 151–161. [Google Scholar] [CrossRef]
- Solomou, K.; Ritter, M.A.; Palmer, D.B. Somatostatin is expressed in the murine thymus and enhances thymocyte development. Eur. J. Immunol. 2002, 32, 1550–1559. [Google Scholar] [CrossRef]
- Silva, A.B.; Aw, D.; Palmer, D.B. Evolutionary conservation of neuropeptide expression in the thymus of different species. Immunology 2006, 118, 131–140. [Google Scholar] [CrossRef]
- Silva, A.B.; Aw, D.; Palmer, D.B. Functional analysis of neuropeptides in avian thymocyte development. Dev. Comp. Immunol. 2008, 32, 410–420. [Google Scholar] [CrossRef]
- Ferone, D.; Pivonello, R.; van Hagen, P.M.; Dalm, V.A.S.H.; Lichtenauer-Kaligis, E.G.R.; Waaijers, M.; van Koetsveld, P.M.; Mooy, D.M.; Colao, A.; Minuto, F.; et al. Quantitative and functional expression of somatostatin receptor subtypes in human thymocytes. Am. J. Physiol. Endocrinol. Metab. 2002, 283, E1056–E1066. [Google Scholar] [CrossRef]
- Ferone, D.; van Hagen, P.M.; van Koetsveld, P.M.; Zuijderwijk, J.; Mooy, D.M.; Lichtenauer-Kaligis, E.G.R.; Colao, A.; Bogers, A.J.J.C.; Lombardi, G.; Lamberts, S.W.J.; et al. In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells. Endocrinology 1999, 140, 373–380. [Google Scholar] [CrossRef]
- Dalm, V.A.; van Hagen, P.M.; van Koetsveld, P.M.; Langerak, A.W.; van der Lely, A.J.; Lamberts, S.W.; Hofland, L.J. Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system. J. Clin. Endocrinol. Metab. 2003, 88, 270–276, Erratum in: J. Clin. Endocrinol. Metab. 2005, 90, 1452. [Google Scholar] [CrossRef] [PubMed]
- Petrović-Dergović, D.M.; Rakin, A.K.; Dimitrijević, L.A.; Ristovski, J.S.; Kustrimović, N.Z.; Mićić, M.V. Changes in thymus size, cellularity and relation between thymocyte subpopulations in young adult rats induced by somatostatin-14. Neuropeptides 2007, 41, 485–493. [Google Scholar] [CrossRef] [PubMed]
- Ryu, S.Y.; Jeong, K.S.; Yoon, W.K.; Park, S.J.; Kang, B.N.; Kim, S.H.; Park, B.K.; Cho, S.W. Somatostatin and substance P induced in vivo by lipopolysaccharide and in peritoneal macrophages stimulated with lipopolysaccharide or interferon-gamma have differential effects on murine cytokine production. Neuroimmunomodulation 2000, 8, 25–30. [Google Scholar] [CrossRef] [PubMed]
- Xidakis, C.; Mastrodimou, N.; Notas, G.; Renieri, E.; Kolios, G.; Kouroumalis, E.; Thermos, K. RT-PCR and immunocytochemistry studies support the presence of somatostatin, cortistatin and somatostatin receptor subtypes in rat Kupffer cells. Regul. Pept. 2007, 143, 76–82. [Google Scholar] [CrossRef]
- Bellocq, A.; Doublier, S.; Suberville, S.; Perez, J.; Escoubet, B.; Fouqueray, B.; Puyol, D.R.; Baud, L. Somatostatin increases glucocorticoid binding and signaling in macrophages by blocking the calpain-specific cleavage of Hsp 90. J. Biol. Chem. 1999, 274, 36891–36896. [Google Scholar] [CrossRef]
- Bhanat, E.; Koch, C.A.; Parmar, R.; Garla, V.; Vijayakumar, V. Somatostatin receptor expression in non-classical locations—clinical relevance? Rev. Endocr. Metab. Disord. 2018, 19, 123–132. [Google Scholar] [CrossRef]
- Reubi, J.C.; Laissue, J.A.; Waser, B.; Steffen, D.L.; Hipkin, R.W.; Schonbrunn, A. Immunohistochemical detection of somatostatin sst2a receptors in the lymphatic, smooth muscular, and peripheral nervous systems of the human gastrointestinal tract: Facts and artifacts. J. Clin. Endocrinol. Metab. 1999, 84, 2942–2950. [Google Scholar] [CrossRef]
- Dalm, V.A.; van Hagen, P.M.; van Koetsveld, P.M.; Achilefu, S.; Houtsmuller, A.B.; Pols, D.H.; van der Lely, A.J.; Lamberts, S.W.; Hofland, L.J. Expression of somatostatin, cortistatin, and somatostatin receptors in human monocytes, macrophages, and dendritic cells. Am. J. Physiol. Endocrinol. Metab. 2003, 285, E344–E353. [Google Scholar] [CrossRef]
- Reubi, J.C.; Schonbrunn, A. Illuminating somatostatin analog action at neuroendocrine tumor receptors. Trends Pharmacol. Sci. 2013, 34, 676–688. [Google Scholar] [CrossRef]
- Vanetti, M.; Kouba, M.; Wang, X.; Vogt, G.; Höllt, V. Cloning and expression of a novel mouse somatostatin receptor (SSTR2B). FEBS Lett. 1992, 311, 290–294. [Google Scholar] [CrossRef]
- Cervia, D.; Bagnoli, P. An update on somatostatin receptor signaling in native systems and new insights on their pathophysiology. Pharmacol. Ther. 2007, 116, 322–341. [Google Scholar] [CrossRef]
- Liu, Q.; Reubi, J.C.; Wang, Y.; Knoll, B.J.; Schonbrunn, A. In vivo phosphorylation of the somatostatin 2A receptor in human tumors. J. Clin. Endocrinol. Metab. 2003, 88, 6073–6079. [Google Scholar] [CrossRef] [PubMed]
- Reubi, J.C.; Kappeler, A.; Waser, B.; Laissue, J.; Hipkin, R.W.; Schonbrunn, A. Immunohistochemical localization of somatostatin receptors sst2A in human tumors. Am. J. Pathol. 1998, 153, 233–245. [Google Scholar] [CrossRef] [PubMed]
- Gugger, M.; Waser, B.; Kappeler, A.; Schonbrunn, A.; Reubi, J.C. Cellular detection of sst2A receptors in human gastrointestinal tissue. Gut. 2004, 53, 1431–1436. [Google Scholar] [CrossRef]
- Bhathena, S.J.; Recant, L. Somatostatin receptors on circulating human blood cells. Horm. Metab. Res. 1980, 12, 277–278. [Google Scholar] [CrossRef]
- Bhathena, S.J.; Louie, J.; Schechter, G.P.; Redman, R.S.; Wahl, L.; Recant, L. Identification of human mononuclear leukocytes bearing receptors for somatostatin and glucagon. Diabetes. 1981, 30, 127–131. [Google Scholar] [CrossRef]
- Reubi, J.C.; Schaer, J.C.; Markwalder, R.; Waser, B.; Horisberger, U.; Laissue, J. Distribution of somatostatin receptors in normal and neoplastic human tissues: Recent advances and potential relevance. Yale J. Biol. Med. 1997, 70, 471–479. [Google Scholar] [PubMed] [PubMed Central]
- de Leeuw, F.E.; Jansen, G.H.; Batanero, E.; van Wichen, D.F.; Huber, J.; Schuurman, H.J. The neural and neuro-endocrine component of the human thymus. I. Nerve-like structures. Brain Behav. Immun. 1992, 6, 234–248. [Google Scholar] [CrossRef]
- Krempels, K.; Hunyady, B.; O’Carroll, A.M.; Mezey, E. Distribution of somatostatin receptor messenger RNAs in the rat gastrointestinal tract. Gastroenterology 1997, 112, 1948–1960. [Google Scholar] [CrossRef]
- Tang, M.; Liu, C.; Li, R.; Lin, H.; Peng, Y.; Lang, Y.; Su, K.; Xie, Z.; Li, M.; Yang, X.; et al. Spatial and temporal expression pattern of somatostatin receptor 2 in mouse. Sheng Wu Gong Cheng Xue Bao. 2023, 39, 2656–2668. (In Chinese) [Google Scholar] [CrossRef]
- Fóris, G.; Gyimesi, E.; Komáromi, I. The mechanism of antibody-dependent cellular cytotoxicity stimulation by somatostatin in rat peritoneal macrophages. Cell Immunol. 1985, 90, 217–225. [Google Scholar] [CrossRef]
- Chao, T.C.; Cheng, H.P.; Walter, R.J. Somatostatin and macrophage function: Modulation of hydrogen peroxide, nitric oxide and tumor necrosis factor release. Regul. Pept. 1995, 58, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Chao, T.C.; Chao, H.H.; Lin, J.D.; Chen, M.F. Somatostatin and octreotide modulate the function of Kupffer cells in liver cirrhosis. Regul. Pept. 1999, 79, 117–124. [Google Scholar] [CrossRef] [PubMed]
- Peluso, G.; Petillo, O.; Melone, M.A.; Mazzarella, G.; Ranieri, M.; Tajana, G.F. Modulation of cytokine production in activated human monocytes by somatostatin. Neuropeptides 1996, 30, 443–451. [Google Scholar] [CrossRef]
- Kang, B.N.; Jeong, K.S.; Park, S.J.; Kim, S.J.; Kim, T.H.; Kim, H.J.; Ryu, S.Y. Regulation of apoptosis by somatostatin and substance P in peritoneal macrophages. Regul. Pept. 2001, 101, 43–49. [Google Scholar] [CrossRef]
- Xidakis, C.; Kolios, G.; Valatas, V.; Notas, G.; Mouzas, I.; Kouroumalis, E. Effect of octreotide on apoptosis-related proteins in rat Kupffer cells: A possible anti-tumour mechanism. Anticancer Res. 2004, 24, 833–841. [Google Scholar] [PubMed]
- Xidakis, C.; Ljumovic, D.; Manousou, P.; Notas, G.; Valatas, V.; Kolios, G.; Kouroumalis, E. Production of pro- and anti-fibrotic agents by rat Kupffer cells; the effect of octreotide. Dig. Dis. Sci. 2005, 50, 935–941. [Google Scholar] [CrossRef]
- Ahmed, A.A.; Wahbi, A.; Nordlind, K.; Kharazmi, A.; Sundqvist, K.G.; Mutt, V.; Lidén, S. In vitro Leishmania major promastigote-induced macrophage migration is modulated by sensory and autonomic neuropeptides. Scand. J. Immunol. 1998, 48, 79–85. [Google Scholar] [CrossRef]
- Valatas, V.; Kolios, G.; Manousou, P.; Xidakis, C.; Notas, G.; Ljumovic, D.; Kouroumalis, E.A. Secretion of inflammatory mediators by isolated rat Kupffer cells: The effect of octreotide. Regul. Pept. 2004, 120, 215–225. [Google Scholar] [CrossRef]
- Kasprzak, A.; Geltz, A. The State-of-the-Art Mechanisms and Anti-tumor Effects of Somatostatin in Colorectal Cancer: A Review. Biomedicines 2024, 12, 578. [Google Scholar] [CrossRef]
- Wu, Y.; Jia, H.; Zhou, H.; Liu, X.; Sun, J.; Zhou, X.; Zhao, H. Immune and stromal related genes in colon cancer: Analysis of tumour microenvironment based on the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. Scand. J. Immunol. 2022, 95, e13119. [Google Scholar] [CrossRef]
- Soetikno, R.; Kaltenbach, T.; McQuaid, K.R.; Subramanian, V.; Kumar, R.; Barkun, A.N.; Laine, L. Paradigm Shift in the Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (West). Dig. Endosc. 2016, 28, 266–273. [Google Scholar] [CrossRef] [PubMed]
- Shah, S.C.; Itzkowitz, S.H. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology. 2022, 162, 715–730.e3. [Google Scholar] [CrossRef] [PubMed]
- Zhang, M.; Li, X.; Zhang, Q.; Yang, J.; Liu, G. Roles of macrophages on ulcerative colitis and colitis-associated colorectal cancer. Front. Immunol. 2023, 14, 1103617. [Google Scholar] [CrossRef] [PubMed]
- van Bergeijk, J.D.; Wilson, J.H. Somatostatin in inflammatory bowel disease. Mediat. Inflamm. 1997, 6, 303–309. [Google Scholar] [CrossRef]
- Lamrani, A.; Tulliez, M.; Chauvelot-Moachon, L.; Chaussade, S.; Mauprivez, C.; Hagnéré, A.M.; Vidon, N. Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis. Aliment. Pharmacol. Ther. 1999, 13, 583–594. [Google Scholar] [CrossRef]
- El-Salhy, M.; Mazzawi, T.; Umezawa, K.; Gilja, O.H. Enteroendocrine cells, stem cells and differentiation progenitors in rats with TNBS-induced colitis. Int. J. Mol. Med. 2016, 38, 1743–1751. [Google Scholar] [CrossRef]
- El-Salhy, M.; Hatlebakk, J.G.; Gilja, O.H. Abnormalities in endocrine and immune cells are correlated in dextran-sulfate-sodium-induced colitis in rats. Mol. Med. Rep. 2017, 15, 12–20. [Google Scholar] [CrossRef]
- Kiviniemi, A.; Gardberg, M.; Kivinen, K.; Posti, J.P.; Vuorinen, V.; Sipilä, J.; Rahi, M.; Sankinen, M.; Minn, H. Somatostatin receptor 2A in gliomas: Association with oligodendrogliomas and favourable outcome. Oncotarget 2017, 8, 49123–49132. [Google Scholar] [CrossRef]
- Di Bella, G.; Leci, J.; Ricchi, A.; Toscano, R. Recurrent Glioblastoma Multiforme (grade IV—WHO 2007): A case of complete objective response—Concomitant administration of Somatostatin/Octreotide, Retinoids, Vit E, Vit D3, Vit C, Melatonin, D2 R agonists (Di Bella Method. Neuro Endocrinol. Lett. 2015, 36, 127–132. [Google Scholar] [PubMed]
- Davies, N.; Kynaston, H.; Yates, J.; Nott, D.M.; Nash, J.; Taylor, B.A.; Jenkins, S.A. Octreotide inhibits the growth and development of three types of experimental liver metastases. Br. J. Surg. 1995, 82, 840–843. [Google Scholar] [CrossRef]
- Davies, N.; Yates, J.; Kynaston, H.; Taylor, B.A.; Jenkins, S.A. Effects of octreotide on liver regeneration and tumour growth in the regenerating liver. J. Gastroenterol. Hepatol. 1997, 12, 47–53. [Google Scholar] [CrossRef] [PubMed]
- Davies, N.; Cooke, T.G.; Jenkins, S.A. Therapeutic potential of octreotide in the treatment of liver metastases. Anticancer Drugs. 1996, 7 (Suppl. S1), 23–31. [Google Scholar] [CrossRef] [PubMed]
- Jenkins, S.A.; Kynaston, H.G.; Davies, N.D.; Baxter, J.N.; Nott, D.M. Somatostatin analogs in oncology: A look to the future. Chemotherapy 2001, 47 (Suppl. S2), 162–196. [Google Scholar] [CrossRef] [PubMed]
- Uhl, W.; Anghelacopoulos, S.E.; Friess, H.; Büchler, M.W. The role of octreotide and somatostatin in acute and chronic pancreatitis. Digestion 1999, 60 (Suppl. S2), 23–31. [Google Scholar] [CrossRef]
- Singh, V.V.; Toskes, P.P. Medical therapy for chronic pancreatitis pain. Curr. Gastroenterol. Rep. 2003, 5, 110–116. [Google Scholar] [CrossRef]
- Khatoon, N.; Zhang, Z.; Zhou, C.; Chu, M. Macrophage membrane coated nanoparticles: A biomimetic approach for enhanced and targeted delivery. Biomater. Sci. 2022, 10, 1193–1208. [Google Scholar] [CrossRef]
- Desai, N.; Rana, D.; Pande, S.; Salave, S.; Giri, J.; Benival, D.; Kommineni, N. "Bioinspired" Membrane-Coated Nanosystems in Cancer Theranostics: A Comprehensive Review. Pharmaceutics 2023, 15, 1677. [Google Scholar] [CrossRef]
- Zheng, J.; Jiang, J.; Pu, Y.; Xu, T.; Sun, J.; Zhang, Q.; He, L.; Liang, X. Tumor-associated macrophages in nanomaterial-based anti-tumor therapy: As target spots or delivery platforms. Front. Bioeng. Biotechnol. 2023, 11, 248421. [Google Scholar] [CrossRef]
Factor | Findings in CRC | Findings Concerning TAMs | Role in Carcinogenesis | Signaling Pathway | Ref. No. |
---|---|---|---|---|---|
EGFR | ↑ (pEGFR, EGFR, iNOS) in AOM/DSS mice vs. NC | (i) ↑ M2 (Arg1, CCL17, CCL22, IL-10, IL-4) and ↓ M1 (iNOS, IL-12, TNF-α, CCR7) markers; (ii) IGF-1 from CRC cells—↑ M2 polarization; (iv) Egfr knockout prevents M1-to-M2 polarization | (i) ↑ Mφ-induced promotion of xenograft tumor growth; (ii) Egfr knockout—↓ cancer cell growth | EGFR | [98] |
↑ In colonic Mφ in the pre-cancerous stages of colitis and dysplasia | (i) ↓ M2 in Egfr-deficient mice—↓ Arg1/IL-10 mRNA and ↓ IL-4/IL-10/IL-13 proteins and ↓ M1; (ii) restrained M1/M2 activation—↓ CXCL1, VEGF, and ↓ CD31+ blood vessels | EGFR signaling in Mφ, but not in colonic epithelial cells, has a significant role in CAC | [99] | ||
CB1 | ↓ CB1 and ↑ EGFR in tumor cells | ↑ CB1 suppressed the differentiation of M2 | ↓ EGFR in CRC—↓ proliferation, migration, and invasion of CRC cells | [100] | |
PCSK9 | (i) ↑ In tumor vs. NC; (ii) ♣ with advanced tumor grade | PCSK9 knockdown—regulation of tumor EMT, ↓ M2 polarization, ↑ M1 polarization by ↓ lactate, protein lactylation, and MIF levels | PCSK9 knockdown—↓ progression and meta of CRC | PI3K/AKT | [101] |
MFHAS1 | ♣ Between expression in TAMs and TNM stage | CRC cells induce M2 polarization of TAMs through ↑ MFHAS1 and ↑ STAT6 and KLF4 | ↑ CRC progression | STAT6/KLF4 | [102] |
CPEB3 | ↓ In tumor ♣ with ↓ CD86+ and ↑ CD163+ TAMs | TAMs enhanced CRC cell proliferation and invasion via IL-6 | Knockdown of CPEB3—↓ tumor progression and M2 polarization in vivo | IL-6R/STAT3 | [103] |
PLXDC1 | (i) ↑ In the tumor; (ii) ♣ with shorter survival | (i) ♣ With M2 markers | Its downregulation may ↓ the progression of CRC | [104] | |
HMGA2 | (i) ♣ With expression in tumor cells and CD68 in the stroma; (ii) ↑ CD68 predicts poor OS | ↑ Mφ recruitment and M2 polarization in vitro and in vivo | ↑ CRC progression | HMGA2/STAT3/CCL2 | [105] |
CTSK | ↑ In tumor ♣ with meta and poor prognosis | (i) ↑ M2 TAMs in the stroma; (ii) bind to TLR4 to ↑ M2 polarization of TAMs | ↑ Invasion and meta of CRC cells | NF-κB/mTOR | [106] |
MET (AMPK agonist) | ↑ (TNF-α and HLA-DR) and ↓ (Arg-1, CD163, CD206) in Mφ incubated with HCT116 | Transforms TAMs to M1 Mφ | ↓ progression of CRC | HIF-1α/p-AKT/mTOR | [107] |
↑ SCFA levels in ETBF/AOM/DSS mice | Modulates M2 polarization (inhibits M0-to-M2 transition) | ↓ Colonic inflammation and colorectal tumorigenesis | TLR4/MyD88/NF-κB/MAPK | [108] | |
PKN2 | (i) ↓ (IL4 and IL10) in tumor cells; (ii) predicts favorable prognosis and ♣ with ↓ M2 in human tumor | ↓ M2 polarization both in vitro and in vivo | (i) ↓ Tumor growth in mice xenografts; (ii) ↓ tumorigenesis | DUSP6/ERK1/2 | [109] |
CD47 | (i) ↑ In tumor; (ii) ↑ IL-10 secretion by tumor cells—↑ M2 Mφ polarization | (i) ↑ Mφ (CD68+) and ↑ M2 Mφ (CD206+); (ii) M2 Mφ secrete immunosuppressive cytokines | ↑ Tumor cell migration and meta | CD47/SIRPα | [92] |
RNASET2 | ↑ In cancer cells | (i) ↑ M1 recruitment and ↓ M2 Mφ; (ii) intra-tumor CD8+ T cells | ↓ Tumor growth by modification of M1/M2 balance ratio, ↓ number of MDSCs, ↓ tumor vessels, and ↑ immune CD8+ T effector cells | N/A | [112] |
TCF4 | (i) ↑ In CRLM vs. primary tumor; (ii) controls CRC-derived CCL2 | (i) ↑ TAM recruitment and M2 polarization in CRLM vs. primary CRC tissues; (ii) ♣ with ↑ TCF4 expression in meta | ↑ Tumorigenesis and progression | TCF4-CCL2-CCR2 | [113] |
CRC-EVs | N/A | (i) SW480 EVs—↓ HLA-DR in M1 and M2, but ↑ CXCL10 in monocytes and M0; (ii) SW620 EVs—↑ (IL-6, CXCL10, IL-23, IL-10) in M0 | Monocyte migration toward the TME and ↑ pro-inflammatory response by TAMs | N/A | [110] |
M1EV1–4 | N/A | TAMs shifted from M2 (CD163+) to M1 (CD68+) Mφ and ↓ (IL-10, TGF-β, CCL22) | M1EV2 and M1EV3 used alone or M1EV4—↓ tumor progression, ↓ primary tumor size and meta | STAT3/NF-κB/AKT | [111] |
Type of ncRNA | Findings in CRC | Findings Concerning TAMs | Role in Carcinogenesis | Signaling Pathway/Molecule | Ref. No. |
---|---|---|---|---|---|
lncRPPH1 | (i) ↑ In tumor; (ii) ♣ with TNM and poor prognosis | TDEs mediate M2 polarization | ↑ Meta and proliferation of CRC cells | ↑ EMT/TUBB3 | [118] |
lncNBR2 | (i) ↓ (NBR2, TNF-α, HLA-DR); (ii) ↑ (Arg-1, CD163, CD206, IL-4) in tumor | ↑ M1 and ↓ M2 polarization in NBR2-overexpressed Mφ | ↓ Progression of CRC in vitro and in vivo | N/A | [136] |
↓ NBR2 and ↑ miR-19a in tumor cells | (i) ↓ M2 polarization by ↓ miR-19a; (ii) NBR2 verified to target miR-19a in Mφ | ↓ Progression of CRC by ↓ miR-19a | miR-19a | [137] | |
lncHLA-F-AS1 | ↑ In tumor | ↑ PFN1 in CRC-EVs by ↓ miR-375—polarizing Mφ toward M2 | ↑ Tumorigenesis; ↑ migration, invasion, and EMT in vitro | miR-375 | [129] |
lncPTTG3P | (i) ↑ In tumor; (ii) ♣ with poor prognosis | Might ↑ cell proliferation, glycolysis through YAP1 and M2 | ↑ CRC progression | YAP1 | [128] |
lncMIR155HG | ↑ In tumor | ↑ M2 polarization | ↑ CRC progression and drug resistance | miR-650/ANXA2 | [130] |
lncHOXB8-1:2 | ↑ In CgA Exo vs. NC Exo | (i) ↑ TAMs and M2 polarization; (ii) in TDEs, it acts as a ceRNA, competitively binding hsa-miR-6825-5p to ↑ CXCR3 | ↑ NE differentiated CRC progression | hsa-miR-6825-5p/CXCR3 | [122] |
lncHCG18 | ↑ in tumor | ↑ M2 polarization to ↑ CET resistance | CET resistance | miR-365a-3p/FOXO1/CSF-1 | [131] |
LINC00543 | (i) ↑ In tumor; (ii) ♣ with TNM stage and poorer prognosis | (i) ↓ Transport of pre-miR-506-3p across the XPO5—↓ miR-506-3p, resulting in ↑ FOXQ1 and ↑ EMT; (ii) ↑ FOXQ1—↑ CCL2 that ↑ Mφ recruitment and their M2 polarization | ↑ CRC progression | pre-miR-506-3p/FOXQ1 | [132] |
lncXIST | ↑ In THP-1 cells after treatment with CT26- and HCT116-derived Exo | ↑ M2 Mφ in TDEs | ↑ Proliferation, migration, and invasion of CRC cells | miR-17-5p/PDGFRA and AKT/ERK/STAT3/6 | [124] |
lncRP11-417E7.1 | (i) ↑ In tumor with lymph node or distant meta; (ii) ♣ with a poor prognosis | (i) TDEs transport THBS2 into Mφ—↑ M2 polarization; (ii) binding with HMGA1—↑ THBS2 transcription | ↑ CRC meta | Wnt/β-catenin/THBS2 | [125] |
lncBANCR | ↑ In serum and tumor vs. adjacent tissues | TDEs (+) regulate the M2 polarization by intake IGF2BP2 | ↑ Cell proliferation, invasion, and meta | RhoA/Rock/IGFBP2 | [126] |
miR-21-5p and miR-200a | ↑ In sEVs | Both ↑ M2 polarization and PD-L1 expression | ↑ Tumor growth | PTEN/AKT and SCOS1/STAT1 | [133] |
miR-216b | ↑ In tumor—↓ (CPEB4, CD206, IL-10) | (i) ↓ M2 polarization; (ii) targets CPEB4 to ↓ IL-10-mediated M2 polarization | ↓ CRC development | N/A | [138] |
miR-4766 | ↑ In hypoxia-treated Mφ | (i) ↓ M2 polarization; (ii) (−) regulates VEGFA | ↓ CRC cell proliferation and migration | VEGFA | [139] |
miR-I48a | (i) ♣ With M2 cytokines; (ii) ↑ expression—↓ Mφ recruited by SW480 cells | (i) ↑ M0-to-M1 differentiation and ↓ M2 polarization; (ii) ↓ TAM intake by targeting SIRPα | (i) ↓ CRC cell viability; anti-tumor effects | SIRPα | [140] |
miR-106a-5p | ↑ In Exo ♣ with CRLM and poor prognosis | (i) ↑ M2 polarization; (ii) hnRNPA1 regulates the transport into Exo | ↑ CRLM | SOCS6/JAK2/STAT3/hnRNPA1 | [127] |
miR-122 | ↑ miR-122 and ↓ NEGR1 in CRLM vs. primary tumors | ↓ NEGR1—↑ M2 polarization and ↑ CRLM in the mouse model | ↑ CRC cell proliferation, migration, and invasion | PI3K/AKT | [134] |
miR-18a | miR-18a encapsulated in GNV—↓ CRLM | miR-18a encapsulated in GNV—↑ M1 Mφ (F4/80+, IFN-γ+, IL-12+) | Anti-meta effect in CRC | N/A | [142] |
circ-0034880 | ↑ In CRC-derived pEVs | TEVs-released circ-0034880—↑ SPP1highCD206+ pro-tumor Mφ | ↑ PMN formation and CRLM | N/A | [135] |
hUC-MSCs-Exos carrying miR-1827 | (i) ↓ SUCNR1 in CRC—↓ tumor cell proliferation, migration, and invasion | ↓ M2 Mφ polarization | (i) ↓ CRC cell growth; (ii) ↓ CRLM in vivo | N/A | [141] |
Factor | Findings in CRC | Findings Concerning TAMs | Role in Carcinogenesis | Signaling Pathway/Molecule | Ref. No. |
---|---|---|---|---|---|
A. muciniphila | ♣ With M1 Mφ and NLRP3/TLR2 | ↑ M1-like Mφ in vivo and in vitro | ↓ CRC development | TLR2/NF-κB/NLRP3 | [145] |
AI-2 from F. nucleatum | ↑ (TNFSF9 and IL-1β) in tumor vs. NC ♣ with AI-2 concentration and ↑ survival | ↑ Mobility and M1 polarization in vitro | Anti-tumor effects | TNFSF9/TRAF1/p-AKT/IL-1β | [150] |
(i) ↑ TNFSF9 in tumor vs. NC; (ii) ♣ with CD3+ cells; (iii) ♣ with CD4/CD8 ratio in tumor | ↑ TNFSF9 in Mφ of TME | Anti-tumor effects | [151] | ||
F. nucleatum | (i) ↓ miR-1322 in CRC cells; (ii) ↑ tumor-derived CCL20 | (i) ↑ Mφ infiltration through ↑ CCL20; (ii) ↑ M2 polarization | ↑ CRC meta and TME reprogramming | miR-1322/NF-κB | [146] |
↑ Tumor-infiltrating M2 Mφ in Fn-positive tumors | (i) ↑ Differentiation M0 to M2 Mφ; (ii) ↑ M2 Mφ | ↑ Cell proliferation, migration, and growth | TLR4/NF-κB/S100A9 | [147] | |
E. coli | ↑ In CRLM | (i) ↑ Lactate—↑ M2 polarization; (ii) RIG-I lactylation in M2 Mφ regulates PD-1+ Tregs and CD8+ T cells in the TME | ↑ Tumor growth and CRLM | RIG-I/MAVS/NF-κB | [152] |
ARCR | N/A | (i) ↓ infiltration of M2 Mφ into TME; (ii) ↓ ZFAS1 by ↓ Sp1 expression to ↓ M2 polarization | ↓ CRC growth and meta in vivo | Sp1/ZFAS1/miR-153-3p/CCR5 | [148] |
Cp (Nem) | ↓ HT-29 cell growth, migration, and invasion | (i) ↓ Viability of M2 Mφ and ↓ MMP-9 activity; (ii) M2 produce soluble factors | ↓ Tumor cell growth | N/A | [90] |
F1 fraction of MEV | ↓ Migration and proliferation of tumor cells | (i) ↑ M1-associated cytokines/markers; (ii) ↓ M2-related markers; (iii) ↑ Mφ phagocytic capacity | Anti-tumor effects in vitro | N/A | [153] |
BBR | (i) Protects against colon shortening in CAC; (ii) ↓ miR-155-5p and ↑ SOCS1 | ↓ The percentage of M1 Mφ and ↓ (IL-1β, IL-6, TNF-α) levels | Anti-tumor effects in the CAC mouse model | miR-155-5p/SOCS1 | [156] |
↑ M2 and ↓ M1 Mφ in the colon and abdomen of DSS-induced UC mice | (i) ↑ (IL-4, STAT6, Chil3) and ↓ (TNF-α, IFN-γ, NOS2) expression in vivo; (ii) ↑ phosphorylation of STAT6 in vivo and in vitro to polarize M2 Mφ | Anti-inflammatory and immune-modulating activities | IL-4/STAT6 | [91] |
Material (No. of Cases) and Methods | Country | Findings | Prognostic Role | Year | Ref. No. |
---|---|---|---|---|---|
↑ TAMs and Favorable Prognosis | |||||
pCRC (5); IHC (manually) | Singapore | (i) ↑ Pro-inflammatory TAMs; (ii) ♣ between tumor-infiltrating T cells and the no. of TAMs | ↑ Mφ infiltration into CRC ♣ with good patient prognoses | 2012 | [75] |
pCRC (485); IHC (manually using a 4-graded scale) | Sweden | (i) (+) ♣ Between the no. of NOS2+ (M1) and CD163+ (M2) cells; (ii) (−) ♣ to tumor stage for both NOS2+ and CD163+ | ↑ Infiltration by NOS2+ cells ♣ with better prognosis (CSS), independent of MSI and CIMP status | 2012 | [74] |
pCRC (210); IHC (digital imaging scanning) | Bulgaria | (i) ↓ CD68+ cells infiltration in tumor stroma ♣ with expression of TGF-β1; (ii) ↓ CD68+ cells ♣ with LN meta, distant meta, ↑ stage, LVI, or perineural invasion | ↓ CD68 appeared to be a significant unfavorable factor for prognosis | 2013 | [163] |
pCRC (205); IHC in next-generation TMA (manually) | Greece | (i) ↑ CD68+ TAMs predicts less tumor budding; (ii) ↑ CD163+ TAMs indicative for < tumor grade; (iii) ↑ CD68+ and CD163+ TAMs ♣ with absence of LN meta | ↑ CD68 ♣ with ↑ OS independent of Mφ polarization, microlocalization, pTNM, and post-operative therapy | 2015 | [165] |
pCRC (419); IHC (computer-automated method) | China | ↑ CD68+TF Mφ ♣ with ↑ CD44v6, ↓ Snail TF, and ↓ tumor buds | ↑ CD68 TF Mφ predicted long-term OS | 2017 | [158] |
pCRC (298); IHC (digital imaging scanning) | Austria | (i) Tumor Mφ with altered phenotype and ↓ CD206+ Mφ vs. control mucosa; (ii) nearly all CD206+ Mφ co-expressed CD163 | ↓ CD206+ Mφ ♣ with a poor prognosis | 2018 | [77] |
pCRC (150); IHC (computer-assisted analysis) | Portugal | (i) CD163+ Mφ mainly at TF, CD80+ Mφ almost exclusively in ANM; (ii) CD163+ Mφ > in stage II, CD80+ Mφ in T1 tumors | (i) In stage III—↑ CD68 and ↓ CD80/CD163 ratio ♣ with ↓ OS; (ii) a protective role of CD80+ Mφ regarding the risk for relapse | 2019 | [166] |
pCRC (931); digital image analysis and machine learning | USA, Finland/Australia | (i) ↑ Intraepithelial and stromal M1 Mφ ♣ with ↑ lymphocytic reactions; (ii) M2 Mφ ♣ with no. of TILs; (iii) MSI-high tumors have ↑ Mφ infiltration adjacent to tumor cells, and ↑ M1-like polarization of stromal Mφ | (i) ↑ Stromal density of M2-like Mφ ♣ with worse CSS; (ii) ↑ M1/M2 density ratio in tumor stroma ♣ with better CCS | 2021 | [159] |
pCRC (64); IHC (Image Pro Plus, and intensity score 0–4) | China | CD86 expression (−) ♣ with tumor differentiation, LN meta, TNM stage, while CD163 expression (+) ♣ with tumor differentiation and tumor size | ↑ CD86+ and CD68+CD86+ TAMs as well as ↓ CD163+ and CD68+ CD163+ TAMs ♣ with favorable OS | 2022 | [80] |
pCRC (150); IHC (manually) | Russia | M2 Mφ—role in limiting the meta-process by affecting vascular maturity and normalization | ↑ CD206 TAMs (+) ♣ with recurrence-free interval duration | 2022 | [81] |
pCRC-TMAs (1720); IHC multiplex fluorescence IHC (digital image analyses) | Norway | (i) ↑ TAM in MSI vs. MSS tumors; (ii) CD68+ TAMs as prognostic markers with clinicopathological and genetic markers | (i) ↑ TAMs ♣ with favorable 5-year RFS in stage I–III; (ii) TAMs ♣ with a good prognosis in pts with ↑ T-cells in tumors; (iii) ↑ TAMs ♣ with poorer prognosis in pts with ↓ T cells; (ii) no difference in the 5-year OS in stage IV according to the no. of CD68 | 2024 | [167] |
↑ TAMs and Unfavorable Prognosis | |||||
pCRC (159); IHC (manually) | Finland | ↓ Intratumoral Stabilin-1+ TAMs among a high no CD68+ Mφ ♣ with a ↓ no. of distant recurrences | ↑ Stabilin-1+ peritumoral Mφ (+) ♣ with longer DFS at stages II and III, but at stage IV—(+) ♣ with ↓ DSS rate | [168] | |
CRC (89); IHC (manually using a 4-graded scale) | Poland | The relative risks of recurrence and CRD were > in pts with ↑ M2 Mφ within the tumor vs. pts with no infiltration | (i) ↑ TAMs in the tumor stroma ♣ with ↓ DFS and OS with the opposite tendency at TF; (ii) TAMs CD68+/iNOS- and Tregs CD8+/FoxP3+ in tumor stroma are (−) prognostic factors with a (+) ♣ between them | 2017 | [164] |
IHC; ELISA; IHC (image analysis software system) | China | (i) Preoperative serum MR and CD163 levels ♣ with serum CEA, CA19-9 and CA72-4 concentrations in CRC pts; (ii) ↑ MR and CD163 in CRC vs. para-cancerous tissues | ↑ MR and CD163 expression in serum ♣ with ↓ OS and shown as adverse prognostic factors | [169] | |
pCRC (81); IHC (manually using immunoreactive score) | China | (i) CD163+ TAMs at TF ♣ with EMT, mesenchymal CTC ratio, and ↓ prognosis; (ii) TAMs—↑ EMT to ↑ CRC migration, invasion, meta by JAK2/STAT3/miR-506-3p/FoxQ1 axis, which leads to the CCL2 production promoting Mφ recruitment | ↑ CD163+ expression ♣ with ↓ OS rate by 30% and ↓ RFS by 20% | 2019 | [170] |
pCRC (81); IHC (manually using immunoreactive score) | China | (i) level of CD163+/CD68+ ratio in TF > in TC; (ii) ↑ CD163+/CD68+TF ratio ♣ with ↑ LVI, tumor invasion, and TNM stage; (iii) ↑ CD163+/CD68+TF ratio ♣ with EMT program and CTCs counts | (i) ↑ CD163+/CD68+TF ♣ with both ↓ RFS and ↓ OS; (ii) CD163+/CD68+TF better prognosticator vs. CD68+TF and CD163+TF; (iii) M2 Mφ secreted TGF-β—↑ EMT, growth, proliferation, and invasion of CRC cells | 2019 | [171] |
CRC biopsies (1008); IHC; prognostic models based on the training cohort (359) | China | pts with well-to-moderate tumor differentiation, fewer numbers of LN meta, TNM stage I or II, or RC tended to have ↑ TANs, ↓ Treg, or TAMs in the three cohorts | (i) TANs, Tregs, TAMs (CD163+) ♣ with worse prognosis and are independent prognostic factors; (ii) pts with ↑ TANs or ↓ Tregs and TAMs had a ↑ DFS and OS, independent of chemotherapy | 2019 | [73] |
stage II CRC (521/314); IHC in TMA (digital imaging scanning) | China | ↑ CD206/CD68 ratio ≥ 0.77 ♣ with LVI and perineural invasion | (i) ↑ CD206/CD68 ratio ♣ with ↓ DFS rate by 40% and OS by 30%; (ii) CD206/CD68 ratio has better prognostic efficacy than CD68+ and CD206+ TAMs, and other clinicopathologic high-risk factors | 2019 | [173] |
submucosal-CRC (87); IHC (computer image analyzer) | Japan | (i) ↑ M2 in TF ♣ with LVI, ↓ histological differentiation, and LN meta; (ii) ↓ M1 in TF ♣ with LN meta; (iii)M2/M1 ratio better predictor of the risk of LN meta vs. pan-, M1, or M2 Mφ at TF | A marker comprising the phenotype, no, and distribution of TAMs may serve as a potential predictor of meta, including LN meta | 2021 | [79] |
pCRC (242); IHC (manually) | China | ↓ M1 (NOS2, CXCL10, CD11c) at TF and TC, while ↑ M2 (CD163, CD206, CD115) mainly at TF | (i) ↓ M1 and ↑ M2 markers exhibited ↓ OS rate; (ii) treble markers combination (NOS2/CXCL10/CD11c or CD163/CD206/CD115) are better predictors than a single marker | 2023 | [160] |
pCRC (10 with CRLM); IHC (image analysis software) | USA | larger tumors (>3.9 cm), ♣ with ↑ total CD68+ Mφ, CD68+CD163+CD206− and CD68+CD206+CD163− M2 Mφ subtypes | ↑ CD68+MRP8-14+CD86- M1 Mφ at TC ♣ with poor OS vs. low densities of this subtype | [96] |
Phenotype of TRMs/TAMs | Normal Colon/Rectum [Ref. No.] | CRC [Ref. No.] |
---|---|---|
M1 | CD68/MHC-II/CD74 [65] | iNOS2/CD68 [76,80,158,163,164,165,166,171], CD86 [77,160,161,169], CD80 [166], CD64 [77,81], MHC-II [161], IL-12/CCR7/TNF-α [76], HLA-DR [77,81], co-expression of NOS2/CXCL10/CD11c [160], co-expression of CD68/CD80/MAF [82] |
M2 | CD68 [65] | CD68 [80,158,163,164,165,166,171], CD163 [74,76,80,164,165,169,170,171], TGF-β [163], Stabilin-1 [76,168], CD204 (MSR1) [76], CD206 (MRC1) [76,77,87,160,161,169], MDSC characteristic gene [87], MHC-II [161], co-expression of CD163/CD206/CD115 [160], co-expression of CD68/MARCO/VEGFA [82], CCL2/18/17/CXCL4 [82], IL-10/Arg1/CCL17/22/IL-4 [76] |
Not specified | LN5/lysozyme/ferritin/α1-antichymotrypsin/25F9 [65], ACP5/C1Q, and LYVE1/COLEC12 [67], IL-4I1/FOLR2 [83] | VEGF [76], C1QC/SPP1 [82,83], IL-4I1/NLRP3 [83], mTORC2 [76] |
Function | Antigen presentation and phagocytosis, regulation of genes related to immune activation and angiogenesis, regulation of genes related to neuronal homeostasis [67]; pathogen clearance, regulation of inflammatory responses, local tissue homeostasis, insulin sensitivity, and chronic inflammation [61]; epithelial self-renewal and metabolic support [68,70] | ↓ Cell proliferation, ↓ production of cytokines (IL-6, IFN-γ) and chemokines (IL-8/CXCL8, CCL2) that attracted T cells and ↑ Th1 cell responses [75]; generation of a precancerous inflammatory environment facilitating the development of cancer [144]; release of pro-tumoral cytokines and chemokines and ↓ ability to activate T cells [161]; role in CAC initiation by ↑ production of cytokines (IL-1β, TNF-α, IL-6) which ↑ the stemness of Dclk1+ tufted cells [58]; ↑ cell proliferation, invasion, facilitating angiogenesis, ↑ tumor progression and metastases [7,79,88,171]; ↑ anti-tumor immune response [7,88]; regulation of metabolism [7]; interaction with microbiota [7,144] |
Positive Role | Drug [Ref. No.] | Promising Targets for Treatment [Ref. No.] | ||
---|---|---|---|---|
Proteins/EVs | ncRNAs | Natural Products | ||
↑ monocyte/Mφ recruitment | CXCR4-CXCL12 inhibitors alone or with durvalumab (anti-PD-L1 Ab) [176]; CCR2/5 (BMS813160) with nivolumab (anti-PD1 Ab) or paclitaxel [62] | TCF4 [113]; HMGA2 in CRC and CAC [105]; CRC-EVs [110] | LINC00543 [132] | F. nucleatum [146] |
↓ monocyte/TAM recruitment | NT157 (IGF-1R inhibitor) [179]; AMG 820 (anti-CSF-1R Ab) [176,197] or with pembrolizumab (CCR5 antagonist) [198]; pexidartinib (PLX3397, CSF-1R inhibitor) alone [176,199] or with durvalumab [176]; pembrolizumab [188] | |||
↑ M0 to M1 polarization | CRC-EVs [110] | miR-I48a [140] | ||
↑ M2 to M1 polarization (reprogramming TAMs) | Maraviroc [177,201]; CET [200]; regorafenib [202]; anti-MARCO IgG [189]; tasquinimod (S100A9 inhibitor) [190]; EZH2 inhibitors [191]; CT-0508 [177]; LIP-F1 and LIP-F2 [183]; pexidartinib alone [177] or with oncolytic viruses, and anti-PD-1 Ab [199] | M1EVs [111] | ||
↑ M1 polarization | EGFR in CAC [99]; RNASET2 [112]; MET [107] | miR-18a [142]; lncNBR2 [136,137] | A. muciniphila [145]; AI-2 from F. nucleatum [150]; F1 fraction of MEV [153] | |
↑ M2 polarization | EGFR in CRC and in CAC [98,99]; HMGA2 in CRC and CAC [105]; CB1 [100]; PCSK9 [101]; MFHAS1 [102]; CPEB3 [103]; PLXDC1 [104]; CTSK [106]; CD47 [92]; TCF4 [113] | lncRPPH1 [118]; lncPTTG3P [128]; lncHLA-F-AS1 [129]; lncMIR155HG [130]; lncHOXB8-1:2 [122]; lncHCG18 [131]; lncXIST [124]; lncRP11-417E7.1 [125]; lncBANCR [126]; LINC00543 [132]; miR-21-5p and miR-200a [133]; miR-106a-5p [127]; miR-122 [134]; circ-0034880 [135] | F. nucleatum [146,147]; E. coli [152]; BBR in CAC [91] | |
↓ M1 formation/polarization | EGFR in CRC and in CAC [98]; PCSK9 [101] | BBR in CAC [91,156] | ||
↓ M2 formation/polarization | PKN2 [109]; RNASET2 [112]; MET [107] | lncNBR2 [136,137]; miR-216b [138]; miR-4766 [139]; miR-I48a [140]; hUC-MSCs-Exos carrying miR-1827 [141] | ARCR [148]; Cp (Nem) [90]; F1 fraction of MEV [153] | |
↓ M0 to M2 transition | MET in CAC [108] | |||
mixed M1/M2 cytokine response | mCRC-EVs [110] | |||
↓ TAM survival (depleting/reducing TAM numbers) | BPR1K871 [180]; pexidartinib (PLX3397) [192]; trifluridine/tipiracil (FTD/TPI) [193]; OXA [193]; M2pep [194]; RG7155 (anti-CSF-1R Ab) [195]; lenvatinib [196] | |||
↑ phagocytic activity of Mφ | Hu5F9-G4 with CET [175,176]; hAB21 alone or with PD-L1 inhibitors [185]; SIRP-1/SIRP-2 Ab, anti-CD47(AO-176) [186] |
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Geltz, A.; Geltz, J.; Kasprzak, A. Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation. Int. J. Mol. Sci. 2025, 26, 5336. https://doi.org/10.3390/ijms26115336
Geltz A, Geltz J, Kasprzak A. Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation. International Journal of Molecular Sciences. 2025; 26(11):5336. https://doi.org/10.3390/ijms26115336
Chicago/Turabian StyleGeltz, Agnieszka, Jakub Geltz, and Aldona Kasprzak. 2025. "Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation" International Journal of Molecular Sciences 26, no. 11: 5336. https://doi.org/10.3390/ijms26115336
APA StyleGeltz, A., Geltz, J., & Kasprzak, A. (2025). Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation. International Journal of Molecular Sciences, 26(11), 5336. https://doi.org/10.3390/ijms26115336