Hypoxia, inflammation, and the tumor microenvironment in metastatic disease

Abstract

Metastasis, the leading cause of cancer deaths, is an intricate process involving many important tumor and stromal proteins that have yet to be fully defined. This review discusses critical components necessary for the metastatic cascade, including hypoxia, inflammation, and the tumor microenvironment. More specifically, this review focuses on tumor cell and stroma interactions, which allow cell detachment from a primary tumor, intravasation to the blood stream, and extravasation at a distant site where cells can seed and tumor metastases can form. Central players involved in this process and discussed in this review include integrins, matrix metalloproteinases, and soluble growth factors/matrix proteins, including the connective tissue growth factor and lysyl oxidase.

Fig. 1

Role of hypoxia and inflammatory-regulated genes on metastasis. The process of metastasis often occurs in regions of oxygen deprivation, termed hypoxia, in which HIF can induce expression of pro-invasive and pro-angiogenic factors, such as LOX, CTGF, VEGF, Ang-2 and decreases in E-cadherin and thrombospondin. Additionally, the inflammatory response induces tumor-associated macrophages which stimulate pro-angiogenic factors, including IL-6, IL-8, and VEGF. Together, hypoxia and inflammation promote an environment permissive of metastatic disease