Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Abstract

Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients. These gradients form through dynamic interactions between the tumor cells and the resident fibroblasts, adipocytes, nerves, endothelial cells, infiltrating immune cells, and mesenchymal stem cells. Malignant progression results from the integrated response of the tumor to these extrinsic physical and chemical cues. Here, we first describe how these physical and chemical gradients develop, and we discuss their role in tumor progression. We then review assays to study these gradients. We conclude with a discussion of clinical strategies used to detect and inhibit these gradients in tumors and of new intervention opportunities. Clarifying the role of these gradients in tumor evolution offers a unique approach to target metastasis.Tumors are highly heterogeneous and this feature compromises treatment efficacy and promotes tumor cell dissemination and metastasis to reduce patient survival. Tumor heterogeneity is driven in part by genetic alterations induced through genomic instability and maintained by the evolutionary selection of these genetically modified cells (Alizadeh et al. 2015). Epigenetic, transcriptional, and posttranslational modifications also contribute significantly to tumor cell diversity. Furthermore, cancer develops within a complex tissue microenvironment that itself fosters tumor heterogeneity through clonal selection as well as via epigenetic reprogramming and modifications of the tumor phenotype. The tumor microenvironment is composed of cellular constituents that include cells of the vasculature, infiltrating immune cells, and resident fibroblasts, adipocytes and nerves, and a noncellular component composed of diverse soluble factors and a highly variable and evolving insoluble extracellular matrix (ECM) (Joyce and Pollard 2009). The composition and organization of the tumor microenvironment vary significantly within and across tumors.One key feature of the noncellular microenvironment is the existence of local chemical and physical gradients that exert profound effects on the tumor phenotype, including its predilection to disseminate. In this regard, metastasis is facilitated by efficient local tumor cell invasion that is fostered by ECM and chemokine/cytokine/growth factor gradients which cooperate to promote the directional migration of the t...

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