The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

Abstract

Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.

Keywords: Cancer progression; Cancer stem cells; Hypoxia; Tumor microenvironment; Tumor treatment.

Fig. 1

The diagram displays the responses to reduced oxygenation within the tumor microenvironment. Hypoxia promotes tumor invasion, metastasis and resistance through several ways. a Hypoxia induces detachment of tumor cells by weakening the connections between cells and their extracellular matrix supporting them, and promotes dissemination of tumor cells to the various organs of the body. Thereby hypoxia triggers the metastatic spread of tumor. b Hypoxia stimulates angiogenesis, and provides more opportunity for detached tumor cell to inter into the circulation and migrate via the newly formed vessels. Thereby hypoxia enhances invasive and metastatic spread of solid tumors to another region. c Hypoxia induces EMT, in which tumor cells detach, lose the epithelial feature, acquire a mesenchymal phenotype and display the stemness properties including loss of differentiation, tumorigenesis and aggressiveness. EMT extensively contributes to promoting of tumor cell invasion and migration. d Hypoxia up-regulates CAFs that produce the excessive altered ECM, which supports tumor growth and metastasis. e Tumor hypoxia promotes secretion of cytokines and chemokines that recruit pro-tumor immune cell and suppress anti-tumor response of various types of immune cells. f In response to hypoxia, tumor cells exploit a number of mechanisms including, extrusion of cytotoxic drug by ABC-transporters, exhibiting quiescent state, acquiring metabolic adaptations and displaying stemness features, which can contribute in chemo-, radio- therapy failure. g Hypoxia acts as a niche condition, to accumulate the CSCs enhancing tumorigenesis and resistance. EMT epithelial to mesenchymal transition, CAF cancer-associated fibroblast, ECM extracellular matrix, MDSCs myeloid-derived suppressor cells, TAM tumor-associated macrophage, TAN tumor-associated neutrophil, Treg regulatory T lymphocyte, NK cell natural killer cell, CSC cancer stem cell