Induction of Cancer Stem Cells in Tumor Microenvironment and Involvement of HIFs And Carbonic Anhydrase IX in Oncogenesis of Solid Tumors and Hematological Malignancies Including Adult T-Cell Leukemia/Lymphoma (ATL)

Review Article

Abstract

Cancer stem cells (CSCs) and leukemia stem cells (LSCs) induced in tumor microenvironment (TME) play important roles in oncogenesis of solid tumors and hematological malignancies. TME contributes to not only induction of CSCs and LSCs but also cancer initiation, proliferation, metastasis and therapy resistance. In addition, hypoxia inducible factors (HIFs) that are induced under hypoxia in TME activate various molecules associated with cancer cell proliferation, survival, metastasis, angiogenesis, immune escape, metabolic regulation and therapy resistance. Carbonic anhydrase IX (CA9) that is one of the gene products induced by HIFs via hypoxia responsive element (HRE) also promotes oncogenesis of solid tumors and hematological malignancies including adult T-cell leukemia/lymphoma (ATL). This review aims to summarize the various mechanisms for induction of CSCs and LSCs in TME and the involvement of HIF and CA9 in oncogenesis of solid tumors and hematological malignancies including ATL. First, we showed induction of CSCs/LSCs by transcription factors, post-transcriptional controls, epigenetic modification, signaling pathways and other extrinsic factors in TME. Then, we indicated the essential roles of HIFs and CA9 in cell proliferation, cell survival, metastasis and therapy resistance. Finally, we shortly discussed the possible therapies to target CSCs, including CA9 inhibitors. From these analyses, it is likely that the HIF-1α/CA9 axis may contribute to finalization of the three-step oncogenesis of ATL