Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Ethical Approval
2.3. Analytical Methods
2.4. Statistical Analysis
3. Results
3.1. ACKR2 and ACKR4 in Colorectal Adenomas
3.1.1. Association with Histological Type
3.1.2. Association with Dysplasia Grade
3.1.3. Association with Adenoma Size and Location
3.1.4. Association with Cumulated Potential for Malignancy
3.2. ACKR2 and ACKR4 in Colorectal Adenocarcinomas
3.2.1. Association with Depth of Tumor Invasion
3.2.2. Association with Lymph Node Metastasis
3.2.3. Association with Tumor Grade
3.2.4. Association with Tumor Location
3.3. ACKR Expression and Malignant Potential Through Adenoma-adenocarcinoma Sequence
3.4. Correlation Patterns with ACKR Ligands
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
- Siegel, R.L.; Miller, K.D.; Goding Sauer, A.; Fedewa, S.A.; Butterly, L.F.; Anderson, J.C.; Cercek, A.; Smith, R.A.; Jemal, A. Colorectal cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 145–164. [Google Scholar] [CrossRef] [Green Version]
- Noel, M.S. Biologics in bowel cancer. J. Gastrointest Oncol. 2017, 8, 449–456. [Google Scholar] [CrossRef] [Green Version]
- Bever, K.M.; Le, D.T. An expanding role for immunotherapy in colorectal cancer. J. Natl. Compr. Cancer Netw. 2017, 15, 401–410. [Google Scholar] [CrossRef]
- Kraus, S.; Arber, N. Inflammation and colorectal cancer. Curr. Opin. Pharmacol. 2009, 9, 405–410. [Google Scholar] [CrossRef] [PubMed]
- Saini, M.K.; Sanya, S.N. Targeting angiogenic pathway for chemoprevention of experimental colon cancer using C-phycocyanin as cyclooxygenase-2 inhibitor. Biochem. Cell Biol. 2014, 92, 206–218. [Google Scholar] [CrossRef] [PubMed]
- Meyskens, F.L., Jr.; McLaren, C.E.; Pelot, D.; Fujikawa-Brooks, S.; Carpenter, P.M.; Hawk, E.; Kelloff, G.; Lawson, M.J.; Kidao, J.; McCracken, J.; et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: A randomized placebo-controlled, double-blind trial. Cancer Prev. Res. 2008, 1, 32–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burke, C.A.; Dekker, E.; Samadder, N.J.; Stoffel, E.; Cohen, A. Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): Design and rationale of a randomized, double-blind, Phase III trial. BMC Gastroenterol. 2016, 16, 87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mukaida, N.; Sasaki, S.; Baba, T. Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment. Mediat. Inflamm. 2014, 2014, 170381. [Google Scholar] [CrossRef]
- Massara, M.; Bonavita, O.; Mantovani, A.; Locati, M.; Bonecchi, R. Atypical chemokine receptors in cancer: Friends or foes? J. Leukoc. Biol. 2016, 99, 927–933. [Google Scholar] [CrossRef] [Green Version]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vacante, M.; Ciuni, R.; Basile, F.; Biondi, A. Gut Microbiota and Colorectal Cancer Development: A Closer Look to the Adenoma-Carcinoma Sequence. Biomedicines 2020, 8, 489. [Google Scholar] [CrossRef] [PubMed]
- McLean, M.H.; Murray, G.I.; Stewart, K.N.; Norrie, G.; Mayer, C.; Hold, G.L.; Thomson, J.; Fyfe, N.; Hope, M.; Mowat, N.A.; et al. The Inflammatory Microenvironment in Colorectal Neoplasia. PLoS ONE 2011, 6, e15366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Q.; Zhu, B.; Li, Y. Resolution of Cancer-Promoting Inflammation: A New Approach for Anticancer Therapy. Front. Immunol. 2017, 8, 71. [Google Scholar] [CrossRef] [Green Version]
- Sjöberg, E.; Meyrath, M.; Chevigné, A.; Östman, A.; Augsten, M.; Szpakowska, M. The diverse and complex roles of atypical chemokine receptors in cancer: From molecular biology to clinical relevance and therapy. Adv. Cancer Res. 2020, 145, 99–138. [Google Scholar] [CrossRef]
- Bonecchi, R.; Graham, G.J. Atypical Chemokine Receptors and Their Roles in the Resolution of the Inflammatory Response. Front. Immunol. 2016, 7, 224. [Google Scholar] [CrossRef] [Green Version]
- Vetrano, S.; Borroni, E.M.; Sarukhan, A.; Savino, B.; Bonecchi, R.; Correale, C.; Arena, V.; Fantini, M.; Roncalli, M.; Malesci, A.; et al. The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut 2010, 59, 197–206. [Google Scholar] [CrossRef]
- Langenes, V.; Svensson, H.; Börjesson, L.; Gustavsson, B.; Bemark, M.; Sjöling, Å.; Quiding-Järbrink, M. Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas. Cancer Immunol. Immunother. 2013, 62, 1687–1695. [Google Scholar] [CrossRef]
- Zhu, Y.; Tang, W.; Liu, Y.; Wang, G.; Liang, Z.; Cui, L. CCX-CKR expression in colorectal cancer and patient survival. Int. J. Biol. Markers 2014, 29, e40-8. [Google Scholar] [CrossRef]
- Vandesompele, J.; De Preter, K.; Pattyn, F.; Poppe, B.; Van Roy, N.; De Paepe, A.; Speleman, F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3, research0034. [Google Scholar] [CrossRef] [Green Version]
- Krzystek-Korpacka, M.; Diakowska, D.; Bania, J.; Gamian, A. Expression stability of common housekeeping genes is differently affected by bowel inflammation and cancer: Implications for finding suitable normalizers for inflammatory bowel disease studies. Inflamm. Bowel. Dis. 2014, 20, 1147–1156. [Google Scholar] [CrossRef] [PubMed]
- Schober, P.; Boer, C.; Schwarte, L.A. Correlation Coefficients: Appropriate Use and Interpretation. Anesth. Analg. 2018, 126, 1763–1768. [Google Scholar] [CrossRef] [PubMed]
- East, J.E.; Atkin, W.S.; Bateman, A.C.; Clark, S.K.; Dolwani, S.; Ket, S.N.; Leedham, S.J.; Phull, P.S.; Rutter, M.D.; Shepherd, N.A.; et al. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut 2017, 66, 1181–1196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fleming, M.; Ravula, S.; Tatishchev, S.F.; Wang, H.L. Colorectal carcinoma: Pathologic aspects. J. Gastrointest. Oncol. 2012, 3, 153–173. [Google Scholar]
- The Human Protein Atlas. Available online: https://www.proteinatlas.org/ENSG00000144648-ACKR2/pathology (accessed on 17 November 2020).
- Hou, T.; Liang, D.; Xu, L.; Huang, X.; Huang, Y.; Zhang, Y. Atypical chemokine receptors predict lymph node metastasis and prognosis in patients with cervical squamous cell cancer. Gyn. Oncol. 2013, 130, 181–187. [Google Scholar] [CrossRef] [Green Version]
- Zeng, X.H.; Ou, Z.L.; Yu, K.D.; Feng, L.Y.; Yin, W.J.; Li, J.; Shen, Z.Z.; Shao, Z.M. Coexpression of atypical chemokine binders (ACBs) in breast cancer predicts better outcomes. Breast Cancer Res. Treat. 2011, 125, 715–727. [Google Scholar] [CrossRef]
- Zhu, Z.; Sun, Z.; Wang, Z.; Guo, P.; Zheng, X.; Xu, H. Prognostic impact of atypical chemokine receptor expression in patients with gastric cancer. J. Surg. Res. 2013, 183, 177–183. [Google Scholar] [CrossRef]
- Wu, F.Y.; Ou, Z.L.; Feng, L.Y.; Luo, J.M.; Wang, L.P.; Shen, Z.Z.; Shao, Z.M. Chemokine decoy receptor d6 plays a negative role in human breast cancer. Mol. Cancer Res. 2008, 6, 1276–1288. [Google Scholar] [CrossRef] [Green Version]
- Shi, J.Y.; Yang, L.X.; Wang, Z.C.; Wang, L.Y.; Zhou, J.; Wang, X.Y.; Shi, G.M.; Ding, Z.B.; Ke, A.W.; Dai, Z.; et al. CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma. J. Pathol. 2015, 235, 546–558. [Google Scholar] [CrossRef]
- Ju, Y.; Sun, C.; Wang, X. Loss of atypical chemokine receptor 4 facilitates C-C motif chemokine ligand 21-mediated tumor growth and invasion in nasopharyngeal carcinoma. Exp. Ther. Med. 2019, 17, 613–620. [Google Scholar] [CrossRef]
- Bednarz-Misa, I.; Diakowska, D.; Krzystek-Korpacka, M. Local and systemic IL-7 concentration in gastrointestinal-tract cancers. Medicina 2019, 55, 262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bednarz-Misa, I.; Diakowska, D.; Szczuka, I.; Fortuna, P.; Kubiak, A.; Rosińczuk, J.; Krzystek-Korpacka, M. Interleukins 4 and 13 and Their Receptors Are Differently Expressed in Gastrointestinal Tract Cancers, Depending on the Anatomical Site and Disease Advancement, and Improve Colon Cancer Cell Viability and Motility. Cancers 2020, 12, 1463. [Google Scholar] [CrossRef] [PubMed]
- Bednarz-Misa, I.; Fortuna, P.; Diakowska, D.; Jamrozik, N.; Krzystek-Korpacka, M. Distinct Local and Systemic Molecular Signatures in the Esophageal and Gastric Cancers: Possible Therapy Targets and Biomarkers for Gastric Cancer. Int. J. Mol. Sci. 2020, 21, 4509. [Google Scholar] [CrossRef] [PubMed]
- Mao, L.; Clark, D. Molecular margin of surgical resections—Where do we go from here? Cancer 2015, 121, 1914–1916. [Google Scholar] [CrossRef]
- Dakubo, G.D.; Jakupciak, J.P.; Birch-Machin, M.A.; Parr, R.L. Clinical implications and utility of field cancerization. Cancer Cell Int. 2007, 7, 2. [Google Scholar] [CrossRef] [Green Version]
- Patel, A.; Tripathi, G.; Gopalakrishnan, K.; Williams, N.; Arasaradnam, R.P. Field cancerisation in colorectal cancer: A new frontier or pastures past? World J. Gastroenterol. 2015, 21, 3763–3772. [Google Scholar] [CrossRef]
- Feng, L.Y.; Ou, Z.L.; Wu, F.Y.; Shen, Z.Z.; Shao, Z.M. Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival. Clin. Cancer Res. 2009, 15, 2962–2970. [Google Scholar] [CrossRef] [Green Version]
- Greystoke, A.; Mullamitha, S.A. How many diseases are colorectal cancer? Gastroenterol. Res. Pract. 2012, 2012, 564741. [Google Scholar] [CrossRef]
- Yamauchi, M.; Lochhead, P.; Morikawa, T.; Huttenhower, C.; Chan, A.T.; Giovannucci, E.; Fuchs, C.; Ogino, S. Colorectal cancer: A tale of two sides or a continuum? Gut 2012, 61, 794–797. [Google Scholar] [CrossRef] [Green Version]
- Simons, C.C.; Hughes, L.A.; Smits, K.M.; Khalid-de Bakker, C.A.; de Bruïne, A.P.; Carvalho, B.; Meijer, G.A.; Schouten, L.J.; van den Brandt, P.A.; Weijenberg, M.P.; et al. A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: Implications for prognosis. Ann. Oncol. 2013, 24, 2048–2056. [Google Scholar] [CrossRef]
- Krzystek-Korpacka, M.; Diakowska, D.; Grabowski, K.; Gamian, A. Tumor location determines midkine level and its association with the disease progression in colorectal cancer patients: A pilot study. Int. J. Colorectal. Dis. 2012, 27, 1319–1324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krzystek-Korpacka, M.; Diakowska, D.; Kapturkiewicz, B.; Bębenek, M.; Gamian, A. Profiles of circulating inflammatory cytokines in colorectal cancer (CRC), high cancer risk conditions, and health are distinct. Possible implications for CRC screening and surveillance. Cancer Lett. 2013, 337, 107–114. [Google Scholar] [CrossRef] [PubMed]
- Krzystek-Korpacka, M.; Zawadzki, M.; Kapturkiewicz, B.; Lewandowska, P.; Bednarz-Misa, I.; Gorska, S.; Witkiewicz, W.; Gamian, A. Subsite heterogeneity in the profiles of circulating cytokines in colorectal cancer. Cytokine 2018, 110, 435–441. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.W.; Tsai, H.L.; Huang, M.Y.; Huang, C.M.; Yeh, Y.S.; Ma, C.J.; Wang, J.Y. Different clinicopathologic features and favorable outcomes of patients with stage III left-sided colon cancer. World J. Surg. Oncol. 2015, 13, 257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Catalano, V.; Loupakis, F.; Graziano, F.; Torresi, U.; Bisonni, R.; Mari, D.; Fornaro, L.; Baldelli, A.M.; Giordani, P.; Rossi, D.; et al. Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy. Br. J. Cancer. 2009, 100, 881–887. [Google Scholar] [CrossRef] [Green Version]
- Phipps, A.I.; Chan, A.T.; Ogino, S. Anatomic subsite of primary colorectal cancer and subsequent risk and distribution of second cancers. Cancer 2013, 119, 3140–3147. [Google Scholar] [CrossRef] [Green Version]
- Savino, B.; Caronni, N.; Anselmo, A.; Pasqualini, F.; Borroni, E.M.; Basso, G.; Celesti, G.; Laghi, L.; Tourlaki, A.; Boneschi, V.; et al. ERK-Dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in Kaposi sarcoma. Cancer Immunol. Res. 2014, 2, 679–689. [Google Scholar] [CrossRef] [Green Version]
Parameter | Characteristics |
---|---|
Sex distribution (F/M), n | 43/53 |
Age (y), mean (95% CI) | 65.1 (62.7–67.4) |
Histological type, n: | |
tubular adenoma | 15 |
tubulovillous adenoma | 60 |
villous adenoma | 13 |
hyperplastic polyps | 8 |
Grade of dysplasia, n: | |
low | 71 |
high | 17 |
Adenoma size, n: | |
<10 mm | 18 |
10–19 mm | 45 |
≥20 mm | 25 |
Polyp location, n: | |
left colon | 48 |
right colon | 25 |
rectum | 23 |
Parameter | Characteristics |
---|---|
Sex distribution (F/M), n | 21/30 |
Age (y), mean (95% CI) | 67.5 (64.5–70.5) |
Cancer TNM stage (0/I/II/III/IV), n | 8/5/11/23/4 |
Depth of tumor invasion (T0-1/T2/T3/T4), n | 8/8/27/8 |
Lymph node metastasis (N0/N1/N2), n | 25/13/13 |
Distant metastasis (M0/M1), n | 47/4 |
Histological grade (G1/G2/G3), n | 4/35/8 |
Primary tumor location, n: | |
left colon | 17 |
right colon | 17 |
rectum | 17 |
Gene | Polyps | Adenocarcinomas |
---|---|---|
CCL2 | r = 0.15, p = 0.170 | r = 0.44, p = 0.002 |
CCL3 | r = 0.41, p < 0.001 | r = 0.54, p < 0.0001 |
CCL4 | r = 0.25, p = 0.022 | r = 0.43, p = 0.002 |
CCL7 | r = 0.27, p = 0.017 | r = 0.52, p = 0.0001 |
CCL8 | r = 0.13, p = 0.253 | r = 0.43, p = 0.002 |
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Lewandowska, P.; Wierzbicki, J.; Zawadzki, M.; Agrawal, A.; Krzystek-Korpacka, M. Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings. Biomolecules 2021, 11, 8. https://doi.org/10.3390/biom11010008
Lewandowska P, Wierzbicki J, Zawadzki M, Agrawal A, Krzystek-Korpacka M. Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings. Biomolecules. 2021; 11(1):8. https://doi.org/10.3390/biom11010008
Chicago/Turabian StyleLewandowska, Paulina, Jaroslaw Wierzbicki, Marek Zawadzki, Anil Agrawal, and Małgorzata Krzystek-Korpacka. 2021. "Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings" Biomolecules 11, no. 1: 8. https://doi.org/10.3390/biom11010008
APA StyleLewandowska, P., Wierzbicki, J., Zawadzki, M., Agrawal, A., & Krzystek-Korpacka, M. (2021). Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings. Biomolecules, 11(1), 8. https://doi.org/10.3390/biom11010008