Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2020 Mar 3

PMID 32118030

Citations 436

Authors

Erik Henke

Rajender Nandigama

Suleyman Ergun

Affiliations

Soon will be listed here.

Abstract

Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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References

Levental K, Yu H, Kass L, Lakins J, Egeblad M, Erler J . Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009; 139(5):891-906. PMC: 2788004. DOI: 10.1016/j.cell.2009.10.027. View

Mintz M, Sowers R, Brown K, Hilmer S, Mazza B, Huvos A . An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res. 2005; 65(5):1748-54. DOI: 10.1158/0008-5472.CAN-04-2463. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Hapke S, Kessler H, Luber B, Benge A, Hutzler P, Hofler H . Ovarian cancer cell proliferation and motility is induced by engagement of integrin alpha(v)beta3/Vitronectin interaction. Biol Chem. 2003; 384(7):1073-83. DOI: 10.1515/BC.2003.120. View

Voloshenyuk T, Landesman E, Khoutorova E, Hart A, Gardner J . Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling. Cytokine. 2011; 55(1):90-7. DOI: 10.1016/j.cyto.2011.03.024. View

Kudo D, Suto A, Hakamada K . The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci. 2017; 18(3). PMC: 5372616. DOI: 10.3390/ijms18030600. View

Qiu X, Tan H, Fu D, Zhu Y, Zhang J . Laminin is over expressed in breast cancer and facilitate cancer cell metastasis. J Cancer Res Ther. 2018; 14(Supplement):S1170-S1172. DOI: 10.4103/0973-1482.191035. View

Li N, Babaei-Jadidi R, Lorenzi F, Spencer-Dene B, Clarke P, Domingo E . An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance. Oncogenesis. 2019; 8(3):13. PMC: 6381143. DOI: 10.1038/s41389-019-0125-3. View

Porsch H, Bernert B, Mehic M, Theocharis A, Heldin C, Heldin P . Efficient TGFβ-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene. 2012; 32(37):4355-65. PMC: 3778714. DOI: 10.1038/onc.2012.475. View

10.

Wei S, Fattet L, Tsai J, Guo Y, Pai V, Majeski H . Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015; 17(5):678-88. PMC: 4452027. DOI: 10.1038/ncb3157. View

11.

Wesley 2nd R, Meng X, Godin D, Galis Z . Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler Thromb Vasc Biol. 1998; 18(3):432-40. DOI: 10.1161/01.atv.18.3.432. View

12.

Koninger J, Giese T, DI Mola F, Wente M, Esposito I, Bachem M . Pancreatic tumor cells influence the composition of the extracellular matrix. Biochem Biophys Res Commun. 2004; 322(3):943-9. DOI: 10.1016/j.bbrc.2004.08.008. View

13.

Sun D, Wang X, Zhang H, Deng L, Zhang Y . MMP9 mediates MICA shedding in human osteosarcomas. Cell Biol Int. 2010; 35(6):569-74. DOI: 10.1042/CBI20100431. View

14.

Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez H, Oyasu M . Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010; 16(9):1009-17. DOI: 10.1038/nm.2208. View

15.

Riaz M, Sieuwerts A, Look M, Timmermans M, Smid M, Foekens J . High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes. Breast Cancer Res. 2012; 14(5):R123. PMC: 4053101. DOI: 10.1186/bcr3317. View

16.

Suhovskih A, Mostovich L, Kunin I, Boboev M, Nepomnyashchikh G, Aidagulova S . Proteoglycan expression in normal human prostate tissue and prostate cancer. ISRN Oncol. 2013; 2013:680136. PMC: 3654277. DOI: 10.1155/2013/680136. View

17.

Toss M, Miligy I, Gorringe K, AlKawaz A, Khout H, Ellis I . Prolyl-4-hydroxylase Α subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS). Br J Cancer. 2018; 119(12):1518-1526. PMC: 6288166. DOI: 10.1038/s41416-018-0337-x. View

18.

Powell J, Mota F, Steadman D, Soudy C, Miyauchi J, Crosby S . Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells. J Med Chem. 2018; 61(9):4135-4154. PMC: 5957473. DOI: 10.1021/acs.jmedchem.8b00210. View

19.

Mammoto T, Jiang A, Jiang E, Panigrahy D, Kieran M, Mammoto A . Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. Am J Pathol. 2013; 183(4):1293-1305. PMC: 3791684. DOI: 10.1016/j.ajpath.2013.06.026. View

20.

Higgins D, Kimura K, Bernhardt W, Shrimanker N, Akai Y, Hohenstein B . Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007; 117(12):3810-20. PMC: 2082142. DOI: 10.1172/JCI30487. View