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Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment.

ABSTRACT: Historically, the link between chronic inflammation and cancer has long been speculated. Only more recently, pre-clinical and epidemiologic data as well as clinical evidence all point to the role of the tumor microenvironment as inextricably connected to the neoplastic process. The tumor microenvironment (TME), a complex mix of vasculature, inflammatory cells, and stromal cells is the essential "soil" helping to modulate tumor potential. Increasingly, evidence suggests that chronic inflammation modifies the tumor microenvironment, via a host of mechanisms, including the production of cytokines, pro-inflammatory mediators, angiogenesis, and tissue remodeling. Inflammation can be triggered by a variety of different pressures, such as carcinogen exposure, immune dysfunction, dietary habits, and obesity, as well as genetic alterations leading to oncogene activation or loss of tumor suppressors. In this review, we examine the concept of the tumor microenvironment as related to both extrinsic and intrinsic stimuli that promote chronic inflammation and in turn tumorigenesis. Understanding the common pathways inherent in an inflammatory response and the tumor microenvironment may shed light on new therapies for both primary and metastatic disease. The concept of personalized medicine has pushed the field of oncology to drill down on the genetic changes of a cancer, in the hopes of identifying individually targeted agents. Given the complexities of the tumor microenvironment, it is clear that effective oncologic therapies will necessitate targeting not only the cancer cells, but their dynamic relationship to the tumor microenvironment as well.

SUBMITTER: Comen EA

PROVIDER: S-EPMC6005853 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment.

Comen Elizabeth A EA Bowman Robert L RL Kleppe Maria M

Frontiers in cell and developmental biology 20180612

Historically, the link between chronic inflammation and cancer has long been speculated. Only more recently, pre-clinical and epidemiologic data as well as clinical evidence all point to the role of the tumor microenvironment as inextricably connected to the neoplastic process. The tumor microenvironment (TME), a complex mix of vasculature, inflammatory cells, and stromal cells is the essential "soil" helping to modulate tumor potential. Increasingly, evidence suggests that chronic inflammation ...[more]

PMID: 29946544

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Project description:Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.

Dataset Information

Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment.

Publications

Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment.

Similar Datasets

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