Hypoxic Tumor Microenvironment and Cancer Cell Differentiation

Abstract

Hypoxia or oxygen deficiency is a salient feature of solid tumors. Hypoxic tumors are often resistant to conventional cancer therapies, and tumor hypoxia correlates with advanced stages of malignancy. Hypoxic tumors appear to be poorly differentiated. Increasing evidence suggests that hypoxia has the potential to inhibit tumor cell differentiation and thus plays a direct role in the maintenance of cancer stem cells. Studies have also shown that hypoxia blocks differentiation of mesenchymal stem/progenitor cells, a potential source of tumor-associated stromal cells. It is therefore likely that hypoxia may have a profound impact on the evolution of the tumor stromal microenvironment. These observations have led to the emergence of a novel paradigm for a role of hypoxia in facilitating tumor progression. Hypoxia may help create a microenvironment enriched in poorly differentiated tumor cells and undifferentiated stromal cells. Such an undifferentiated hypoxic microenvironment may provide essential cellular interactions and environmental signals for the preferential maintenance of cancer stem cells. This hypothesis suggests that effectively targeting hypoxic cancer stem cells is a key to successful tumor control.

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“…Interestingly, both CTGF and Igfbp5 have been independently found to inhibit osteoblast maturation and differentiation [63,64] while MGP is an ECM protein that has been shown to inhibit mineralization and apoptosis of chondrocytes [65]. These findings suggest that interactions between leukemia and the BM stroma induce changes towards an undifferentiated state of the tumor microenvironment that could contribute to disease progression and chemotherapy resistance [66]. Furthermore, our findings indicate upregulation of genes related to complement (C4A, C4B, and SERPING1) in BM-MSC exposed to leukemia in vivo.…”

Cross‐Talk Between Hypoxia and the Tumour via Exosomes

“…The lowered blood supply indicates a lower number of red blood cells being able to reach the tumour cells resulting in decreased oxygen delivery [52]. Moreover, hypoxic tumours have a greater ability to resist standard treatments and the tumour cells are often in a less differentiated or more stem cell-like state [53]. Emerging evidence has shown that exosomes are key membrane vesicles secreted by most cell types under hypoxia.…”

Tumor Microenvironment in Head and Neck Squamous Cell Carcinomas

“…Hypoxia in the head and neck squamous cell carcinoma tumor microenvironment: mechanisms, effects, diagnostic methods and clinical significance When compared with the healthy tissues around many solid tumor microenvironments, such as breast, brain, cervix, prostate, rectum, and head and neck cancers, a significant level of hypoxia has been demonstrated (38). Heterogeneously distributed hypoxic areas at different levels were found in the microenvironment of 50-60% of locally advanced tumors (35).…”