Crosstalk between CTC, Immune System and Hypoxic Tumor Microenvironment

Abstract

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.

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

“…Immune escape and suppression are important phenomena and have long been proposed to constitute critical steps in both tumor formation and progression . Theoretically, cancer cells that exit the primary tumor tissue, and thus leave the protection of the immunosuppressive tumor microenvironment, are more vulnerable to attack by immune effector cells . Therefore, the survival of CTCs might be a vulnerable aspect of malignant tumor metastasis, and thus the mechanism enabling CTCs to evade immune effector cell killing may be an important target for prospective cancer therapy research.…”

The hypoxic microenvironment: A determinant of cancer stem cell evolution

“…EMT is one of the initiating factors of circulating tumor cells (CTCs) and is required for their capacity to migrate into blood vessels. Several studies have demonstrated the upregulation of EMT markers in CTCs, supporting this hypothesis . CTCs expressing vimentin and Twist were identified in breast cancer patients, and the presence of CTCs was correlated with metastatic disease, confirming that EMT is involved in the metastatic potential of CTCs .…”

“…These studies also showed a preferential role for HIF‐2α in the selective eradication of CSCs without adverse effects on normal progenitor cells. However, recent evidence in human leukemia showed selective activation of HIF‐1α in CSCs under normoxic conditions due to VHL deficiency, and blocking of HIF‐1α activity was necessary to sustain leukemia stem cell survival but not that of normal hematopoietic stem cells .…”

“…HIF‐1α and HIF‐2α themselves, and transcriptional hypoxic signatures, have been correlated with aggressive tumor behavior, adverse prognosis and resistance to therapy . Clinical evidence also suggests that patients with tumors that contain more extensive hypoxic and anoxic areas have higher rates of metastases .…”

Circulating Tumour Cells in Predictive Molecular Pathology: Focus on Drug-Sensitive Assays and 3D Culture

“…The formation of microemboli results from the increased adhesive capacity of CTCs, and improves the metastatic potential of these cells. Notably, CTCs elude the immune system through many immune checkpoint inhibitor systems such as programmed cell death protein 1 and programmed death-ligand 1 [31, 32]. …”