The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Abstract

The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis.

Keywords: cancer therapy; drug delivery; immune system; metastasis; tumor microenvironment.

Figure 1

Pharmaceutical regulation of the TME at various stages of the metastatic process. At the primary tumor site, JWH-015, a CB agonist, blocks macrophage recruitment, while other agents inhibit the interaction between CSFR and CSF produced by cancer cells. Bisphosphonates can block MMPs produced by CAFs and other types of cells and impair cancer cell invasion. CAIX produced under hypoxic conditions may be inhibited by small molecules, like AAZ. In the blood TME, blocking platelet interaction with CTCs as well as regulating cytokine content, such as of IL-17A, can effectively reduce metastatic burden. At the secondary site, bisphosphonates, including clodronate, can reduce the number of TAMs. Exosomes produced by manipulated MSCs can deliver anticancer therapeutics, such as Taxol, to inhibit distant metastases. INF-γ blocks the polarization of M1 macrophages to the M2-tumor promoting phenotype. Galunisertib can inhibit TGF-β signaling induced in the tumor by CAFs and is effective when combined with anti-PD-1 therapy, to promote T-cell activation.

Figure 2

Strategies to improve tumor oxygenation and therapeutic efficacy in primary and metastatic tumors. A desmoplastic TME is defined by excess ECM and dysfunctional vasculature. Abundantly found stromal structures, like collagen and hyaluronan, promote the development of compressive forces leading to blood vessel collapse, which in turn causes hypo-perfusion and hypoxia. In addition, the abnormally large vessel pores of some tumor vessels enhance fluid leakage to the interstitial space that further contributes to hypo-perfusion and hypoxia. Hypoxia recruits immunosuppressive immune cells, such as M2-macrophages, which in combination with T-cell exclusion and CAFs activation promote metastasis. Stroma and vessel normalization strategies aim to alleviate intratumoral forces and stiffness, decompress vessels, improve perfusion and heterogeneous delivery of chemo- and nano-therapeutic agents. Re-establishment of adequate oxygenation within the TME potentiates T cell infiltration, immunostimulation and suppresses metastasis.