Role of the Hypoxic-Secretome in Seed and Soil Metastatic Preparation

Simple Summary During tumor growth the aberrant or absent vasculature causes hypoxia, an important decrease in the supply of oxygen to the cells that causes an adaptative response in the microenvironment of the tumor. Hypoxia activates the expression of genes that control several essential cellular processes. Among others, hypoxia induces the expansion of cancer stem cell (CSC) pools and promotes the transcription and secretion of factors that will adapt niches in different organs to receive, proliferate and promote the survival of malignant cells from the primary tumor, forming metastasis. CSCs at the secondary site also interact with stromal cells in the secondary organ to promote metastasis. Several cytokines released by cells within the secondary tumor microenvironment determine the tissue inflammatory infiltration and the cancer-associated phenotype of the immune component. Therefore, hypoxia initiates a cascade of physiological responses that not only affect the primary tumor, but also prepare secondary niches in distant organs for the apparition and development of metastasis. During tumor growth, the delivery of oxygen to cells is impaired due to aberrant or absent vasculature. This causes an adaptative response that activates the expression of genes that control several essential processes, such as glycolysis, neovascularization, immune suppression, and the cancer stemness phenotype, leading to increased metastasis and resistance to therapy. Hypoxic tumor cells also respond to an altered hypoxic microenvironment by secreting vesicles, factors, cytokines and nucleic acids that modify not only the immediate microenvironment but also organs at distant sites, allowing or facilitating the attachment and growth of tumor cells and contributing to metastasis. Hypoxia induces the release of molecules of different biochemical natures, either secreted or inside extracellular vesicles, and both tumor cells and stromal cells are involved in this process. The mechanisms by which these signals that can modify the premetastatic niche are sent from the primary tumor site include changes in the extracellular matrix, recruitment and activation of different stromal cells and immune or nonimmune cells, metabolic reprogramming, and molecular signaling network rewiring. In this review, we will discuss how hypoxia might alter the premetastatic niche through different signaling molecules.

Automated summary

During tumor growth, hypoxia triggers a cascade of physiological responses that affect the primary tumor and prepare distant organs for the development of metastasis. This adaptive response induces the expansion of cancer stem cells, promotes metastasis, and alters the microenvironment to facilitate the attachment and growth of tumor cells. Hypoxia-induced signaling molecules play a crucial role in modifying the premetastatic niche.