Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers
Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, ga...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.837585/full |
| _version_ | 1818982286344847360 |
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| author | William L. Harryman Kendra D. Marr Kendra D. Marr Kendra D. Marr Ray B. Nagle Ray B. Nagle Anne E. Cress Anne E. Cress |
| author_facet | William L. Harryman Kendra D. Marr Kendra D. Marr Kendra D. Marr Ray B. Nagle Ray B. Nagle Anne E. Cress Anne E. Cress |
| author_sort | William L. Harryman |
| collection | DOAJ |
| description | Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies. |
| first_indexed | 2024-12-20T17:44:48Z |
| format | Article |
| id | doaj.art-857836f9ed074891895f30fee0c00ef0 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-20T17:44:48Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-857836f9ed074891895f30fee0c00ef02022-12-21T19:31:01ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-03-011010.3389/fcell.2022.837585837585Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal CancersWilliam L. Harryman0Kendra D. Marr1Kendra D. Marr2Kendra D. Marr3Ray B. Nagle4Ray B. Nagle5Anne E. Cress6Anne E. Cress7Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United StatesCancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United StatesCancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United StatesMedical Scientist Training Program, College of Medicine, University of Arizona, Tucson, AZ, United StatesCancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United StatesDepartment of Pathology, College of Medicine, University of Arizona, Tucson, AZ, United StatesCancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United StatesDepartment of Cellular and Molecular Medicine and Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, United StatesMuscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.https://www.frontiersin.org/articles/10.3389/fcell.2022.837585/fullintegringrowth factormuscle invasioncadherinepithelial mesenchymal cooperation |
| spellingShingle | William L. Harryman Kendra D. Marr Kendra D. Marr Kendra D. Marr Ray B. Nagle Ray B. Nagle Anne E. Cress Anne E. Cress Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers Frontiers in Cell and Developmental Biology integrin growth factor muscle invasion cadherin epithelial mesenchymal cooperation |
| title | Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers |
| title_full | Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers |
| title_fullStr | Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers |
| title_full_unstemmed | Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers |
| title_short | Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers |
| title_sort | integrins and epithelial mesenchymal cooperation in the tumor microenvironment of muscle invasive lethal cancers |
| topic | integrin growth factor muscle invasion cadherin epithelial mesenchymal cooperation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.837585/full |
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