Crosstalk between CTC, Immune System and Hypoxic Tumor Microenvironment.

Accumulating evidence indicate that the behavior of tumorigenic cells is highly influenced by their microenvironment. In this regard, microenvironmental hypoxia plays a determinant role in the emergence of CTC (circulating tumor cells) and CSC (cancer stem cells). CTCs are believed to be indicators of residual disease and thus pose an increased risk of metastasis. In spite of being rare and exposed to immune attack, these cells are capable to escape the immune system of the host. Although CTC play a pivotal role in the metastatic cascade and their prognostic impact has been repeatedly demonstrated, little is known about their escape mechanisms to immune system of the host. Therefore a better knowledge of the immunogenicity of these cells and their cross talk with immune killer cells as well as with tumor microenvironment may represent an exciting new immunotherapy opportunity. In this chapter, we will discuss how hypoxia is involved in the regulation of tumor progression and induction of EMT and cancer stem cell like features. We will also illustrate the relationship between hypoxia and CTC and review how CTC interact with the cells of immune system (both innate and adaptive) in terms of their survival and EMT phenotype. We will attempt to outline how hypoxic stress may confer resistance to CTC by giving them EMT and CSC like phenotype. Finally we will discuss whether the inhibition of hypoxic signaling pathways in different compartments of the solid tumor microenvironment will have an impact on CTC number, resistant phenotype and CTC lysis by immune effectors.