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Understanding the Role of the Microenvironment in the Progression of Tumors

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 50576

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Special Issue Editors

Dr. Ignacio Ochoa

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Guest Editor

Tissue Microenvironment Lab (TME), Aragón Institute of Engineering Research (I3A), University of Zaragoza, 50018 Zaragoza, Spain Institute for Health Research Aragon (IIS Aragón), 50009 Zaragoza, Spain
Biomedical Research Networking center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 50018 Zaragoza, Spain
Interests: Tumor microenvironment; In vitro biomimetic models (cancer on chip); In silico models; Cancer progression; Tumor heterogeneity

Prof. Dr. José María Ayuso-Dominguez

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Guest Editor

Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53715, USA
Interests: microfluidics; cancer; microphysiological systems; immunology; immunotherapy

Special Issue Information

Dear Colleagues,

Tumor cells coexist and communicate with the rest of the cells present in the tissue where the tumor is generated. Stromal fibroblasts, the various cell types of the blood vessels, and the immune system cells also play an essential role in tumor progression. However, in addition to the cellular components of the tissues, other environmental factors are capable of altering the fragile balance of tumors (oxygen, extracellular matrix deposition, pH, interstitial pressure, etc.). All these previously mentioned factors (cellular and non-cellular) form what is known as the tumor microenvironment.

This tumor microenvironment is always in a fragile balance and is dynamic over time. The capacity of the different cells to adapt to the new environmental conditions generated throughout the progression of the tumor can cause changes that condition the phenotype of the tumor cells. Hypoxia, the appearance of necrotic areas, the infiltration of cells of the immune system, or the deposition of proteins from the extracellular matrix are some alterations that can appear in different regions of the tumor. Additionally, these changes are dependent on the local microenvironment, which causes differences between areas, thus generating tumor heterogeneity.

Non-homogeneous environmental conditions and tumor heterogeneity are critical aspects of tumor progression and in the appearance between tumor cells of resistance mechanisms to the treatments applied in the clinic. This Special Issue will highlight the role of the different players of the tumor microenvironment in cancer progression, covering both basic and more (pre) clinical aspects to improve our understanding of these complex interactions in human tumors.

Dr. Ignacio Ochoa
Dr. José María Ayuso-Dominguez
Guest Editors

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Keywords

Tumor microenvironment
Immune system
Cancer Associated Fibroblasts
Tumor angiogenesis
Tumor Hypoxia
Tumor gradients
Drug resistance
Tumor cell plasticity
Cancer progression

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 200 KiB

Open AccessEditorial

The Importance of the Tumor Microenvironment to Understand Tumor Origin, Evolution, and Treatment Response

by Jose M. Ayuso and Ignacio Ochoa Garrido

Cancers 2022, 14(8), 1983; https://doi.org/10.3390/cancers14081983 - 14 Apr 2022

Cited by 3 | Viewed by 1798

Abstract

During the second half of the twentieth century, oncology adopted a tumor-centric approach to cancer treatment, focusing primarily on the tumor cell to identify new therapeutic targets [...] Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

Research

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17 pages, 1411 KiB

Open AccessArticle

The Effect of Hypoxia on Relative Biological Effectiveness and Oxygen Enhancement Ratio for Cells Irradiated with Grenz Rays

by Chun-Chieh Chan, Fang-Hsin Chen, Kuang-Lung Hsueh and Ya-Yun Hsiao

Cancers 2022, 14(5), 1262; https://doi.org/10.3390/cancers14051262 - 28 Feb 2022

Cited by 4 | Viewed by 2606

Abstract

Grenz-ray therapy (GT) is commonly used for dermatological radiotherapy and has a higher linear energy transfer, relative biological effectiveness (RBE) and oxygen enhancement ratio (OER). GT is a treatment option for lentigo maligna and lentigo maligna melanoma. This study aims to calculate the RBE for DNA double-strand break (DSB) induction and cell survival under hypoxic conditions for GT. The yield of DSBs induced by GT is calculated at the aerobic and hypoxic conditions, using a Monte Carlo damage simulation (MCDS) software. The RBE value for cell survival is calculated using the repair–misrepair–fixation (RMF) model. The RBE values for cell survival for cells irradiated by 15 kV, 10 kV and 10 kVp and titanium K-shell X-rays (4.55 kV) relative to ⁶⁰Co γ-rays are 1.0–1.6 at the aerobic conditions and moderate hypoxia (2% O₂), respectively, but increase to 1.2, 1.4 and 1.9 and 2.1 in conditions of severe hypoxia (0.1% O₂). The OER values for DSB induction relative to ⁶⁰Co γ-rays are about constant and ~2.4 for GT, but the OER for cell survival is 2.8–2.0 as photon energy decreases from 15 kV to 4.55 kV. The results indicate that GT results in more DSB induction and allows effective tumor control for superficial and hypoxic tumors. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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16 pages, 2149 KiB

Open AccessArticle

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

by Shreyans Sadangi, Katarina Milosavljevic, Edgardo Castro-Perez, Marcos Lares, Mithalesh Singh, Sarah Altameemi, David J. Beebe, Jose M. Ayuso and Vijayasaradhi Setaluri

Cancers 2022, 14(5), 1233; https://doi.org/10.3390/cancers14051233 - 27 Feb 2022

Cited by 9 | Viewed by 3517

Abstract

BRAF^V600E is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor PTEN and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the BRAF^V600E mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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17 pages, 3091 KiB

Open AccessArticle

Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer

by Patrick N. Song, Ameer Mansur, Yun Lu, Deborah Della Manna, Andrew Burns, Sharon Samuel, Katherine Heinzman, Suzanne E. Lapi, Eddy S. Yang and Anna G. Sorace

Cancers 2022, 14(4), 1015; https://doi.org/10.3390/cancers14041015 - 17 Feb 2022

Cited by 8 | Viewed by 2992

Abstract

DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [¹⁸F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [¹⁸F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [¹⁸F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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24 pages, 3670 KiB

Open AccessArticle

Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation

by Rebeca E. Nuñez, Miguel Mayol del Valle, Kyle Ortiz, Luis Almodovar and Lilia Kucheryavykh

Cancers 2021, 13(24), 6160; https://doi.org/10.3390/cancers13246160 - 7 Dec 2021

Cited by 18 | Viewed by 3408

Abstract

Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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23 pages, 4259 KiB

Open AccessArticle

A Novel Orthotopic Liver Cancer Model for Creating a Human-like Tumor Microenvironment

by Rong Qiu, Soichiro Murata, Chao Cheng, Akihiro Mori, Yunzhong Nie, Satoshi Mikami, Shunsuke Hasegawa, Tomomi Tadokoro, Satoshi Okamoto and Hideki Taniguchi

Cancers 2021, 13(16), 3997; https://doi.org/10.3390/cancers13163997 - 8 Aug 2021

Cited by 15 | Viewed by 5017

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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24 pages, 3856 KiB

Open AccessArticle

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

by Eva Balaziova, Petr Vymola, Petr Hrabal, Rosana Mateu, Michal Zubal, Robert Tomas, David Netuka, Filip Kramar, Zuzana Zemanova, Karla Svobodova, Marek Brabec, Aleksi Sedo and Petr Busek

Cancers 2021, 13(13), 3304; https://doi.org/10.3390/cancers13133304 - 1 Jul 2021

Cited by 25 | Viewed by 4487

Abstract

Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP⁺ stromal cells are mostly localised in the vicinity of activated CD105⁺ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP⁺ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP⁺ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP⁺ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP⁺ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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19 pages, 2775 KiB

Open AccessArticle

Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

by Russell Hughes, Xinyue Chen, Natasha Cowley, Penelope D. Ottewell, Rhoda J. Hawkins, Keith D. Hunter, Jamie K. Hobbs, Nicola J. Brown and Ingunn Holen

Cancers 2021, 13(6), 1366; https://doi.org/10.3390/cancers13061366 - 18 Mar 2021

Cited by 10 | Viewed by 3117

Abstract

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER⁺) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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Graphical abstract

16 pages, 4756 KiB

Open AccessArticle

High-Plex and High-Throughput Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)

by James Monkman, Touraj Taheri, Majid Ebrahimi Warkiani, Connor O’Leary, Rahul Ladwa, Derek Richard, Ken O’Byrne and Arutha Kulasinghe

Cancers 2020, 12(12), 3551; https://doi.org/10.3390/cancers12123551 - 27 Nov 2020

Cited by 35 | Viewed by 7822

Abstract

Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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Review

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31 pages, 2351 KiB

Open AccessReview

Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

by Nan Sethakorn, Erika Heninger, Cristina Sánchez-de-Diego, Adeline B. Ding, Ravi Chandra Yada, Sheena C. Kerr, David Kosoff, David J. Beebe and Joshua M. Lang

Cancers 2022, 14(3), 757; https://doi.org/10.3390/cancers14030757 - 1 Feb 2022

Cited by 19 | Viewed by 6543

Abstract

Bone metastases represent a lethal condition that frequently occurs in solid tumors such as prostate, breast, lung, and renal cell carcinomas, and increase the risk of skeletal-related events (SREs) including pain, pathologic fractures, and spinal cord compression. This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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11 pages, 4176 KiB

Open AccessReview

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications

by Ángela Bella, Claudia Augusta Di Trani, Myriam Fernández-Sendin, Leire Arrizabalaga, Assunta Cirella, Álvaro Teijeira, José Medina-Echeverz, Ignacio Melero, Pedro Berraondo and Fernando Aranda

Cancers 2021, 13(5), 963; https://doi.org/10.3390/cancers13050963 - 25 Feb 2021

Cited by 15 | Viewed by 7541

Abstract

Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents. Full article

(This article belongs to the Special Issue Understanding the Role of the Microenvironment in the Progression of Tumors)

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