Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression

Abstract

Treatment of cancer metastasis has been largely ineffective. It is paramount to understand the mechanisms underlying the metastatic process, of which the tumor microenvironment is an indispensable participant. What are the critical cellular and molecular players at the primary tumor site where metastatic cascade initiates? How is tumor-associated inflammation regulated? How do altered vasculatures contribute to metastasis? What is the dynamic nature or heterogeneity of primary tumors and what are the challenges to catch a moving target? This review summarizes recent progress, mechanistic understanding, and options for metastasis-targeted therapy.

Keywords: Heterogeneity; Inflammation/Immune; Microenvironment; Tumor metastasis; Tumor suppressor.

Fig. 1

Players in the TME and the outcome resulting from tumor-associated inflammation. CAFs: cancer-associated fibroblasts; CTL: cytotoxic T cells; DC: dendritic cells; EPCs: endothelial progenitor cells; MDSC: Gr-1+CD11b+ myeloid-derived suppressor cells; Neu: neutrophiles; NK: natural killer cells; TAM: tumor-associated macrophages; Treg: regulatory T cells.

Fig. 2

Loss of TS and/or activation of oncogenes (input, black arrows) induces the inflammatory microenvironment. Loss of p53, TGFβ, APC, and PTEN, and/or activation of K-ras, RET, and RTK induces infiltration of host-derived inflammatory and stromal cells (in the big circle), and increases expression of growth factors, cytokines, chemokines, production of prostaglandins, reactive oxygen, and nitrogen species. The underlying mechanisms involve NF-κB and STAT3 signaling pathways.

Fig. 3

TME promotes tumor heterogeneity through genomic instability, epigenetic alterations, splice variants, and soluble factors produced by inflammatory cells, stromal cells, and endothelial cells in the TME.

Fig. 4

Targeting opportunities (green color) aimed at inflammation and the TME. IKKβ or IKKα inhibitors, Metformin, as well as anti-inflammation drugs can be combined with conventional chemotherapeutic agents, radiation therapies, and targeted therapies. Immunotherapy and neutralization antibodies and antagonists have shown efficacy in targeting soluble factors. Vasculature targeting and cell type specific targeting offer additional options to inhibit the inflammatory TME and enhance host anti-tumor immunity.