The Interplay of the Extracellular Matrix and Stromal Cells as a Drug Target in Stroma-Rich Cancers

Abstract

The tumor microenvironment (TME) is a complex neighborhood that consists of immune cells, fibroblasts, pericytes, adipocytes, endothelial and neuronal cells, and the extracellular matrix proteins. TME also consists of physical factors, such as oxygen availability, changing pH, interstitial fluid pressure, and tissue stiffness. As cancer progresses, the physical properties and the cells in the TME change significantly, impacting the efficacy of the therapies and modulating drug resistance. This has led to the development of several new treatments targeting the TME. This review focuses on recent advances on the role of TME in drug resistance, with a particular focus on the ongoing clinical trials aiming at disrupting the TME- and the extracellular matrix-mediated protection against therapies.

Keywords: cancer-associated fibroblasts; clinical trials; drug resistance; extracellular matrix; stroma-cancer crosstalk; tumor microenvironment.

Figure 1:. Components of the tumor microenvironment (TME)

Cancer cells are surrounded by various cell types: fibroblasts, adipocytes, endothelial cells, pericytes, neurons and immune cells. The dense ECM that the tumors adhere to serves as a storage for growth factors, cytokines, lipids, proteases and metabolites, secreted by the cells of the TME. As tumor grows, the physical properties in the tumor core like oxygen and nutrient levels, pH, stiffness, and pressure become different from those on the edge of the tumor. These changes, so as the differences in matrix composition and alignment, influence the properties and behavior of other cell types in the TME, thus influencing drug penetrance, drug resistance and disease outcome.

Figure 2:. Current strategies to target tumor stroma in clinical trials

Different strategies currently used in the clinic or in clinical trials to target stroma in cancer include A) increasing anti-tumor immunity by targeting secreted factors (e.g. CXCL12, CSF1) that decrease the presence of TAMs and increase the infiltration of cytotoxic T lymphocytes; B) targeting ECM-cell adhesion molecules such as integrins, Src and FAK kinases (often in combination with other drugs) to reduce tumor cell fitness and tumor drug resistance to other therapies; C) targeting matrix proteins such as Hyaluronic acid and connective tissue growth factor (CTGF) to normalize tumor stroma and interstitial pressure and to normalize vasculature and reduce hypoxia, and to increase delivery of chemotherapies and increase the access of immune cells; D) use of anti-fibrotics and TGFβ inhibitors to reduce fibrosis, increase drug delivery, normalize vasculature, reverse hypoxia and increase immune cell infiltration; E) use of VEGF inhibitors, to normalize vasculature and increase cytotoxic T lymphocyte and immune cell infiltration.