HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia

Abstract

The standard treatment for Glioblastoma multiforme (GBM) is surgical resection and subsequent radiotherapy and chemotherapy. Surgical resection of GBM is typically restricted because of its invasive growth, which results in residual tumor cells including glioma stem cells (GSCs) and differentiated cells. Recurrence has been previously thought to occur as a result of these GSCs, and hypoxic microenvironment maintains the GSCs stemness also plays an important role. Summarizing traditional studies and we find many researchers ignored the influence of hypoxia on differentiated cells. We hypothesized that the residual differentiated cells may be dedifferentiated to GSC-like cells under hypoxia and play a crucial role in the rapid, high-frequency recurrence of GBM. Therefore, isolated CD133–CD15–NESTIN– cells were prepared as single-cell culture and treated with hypoxia. More than 95% of the surviving single differentiated CD133–CD15–NESTIN– cell dedifferentiated into tumorigenic CD133+CD15+NESTIN+ GSCs, and this process was regulated by hypoxia inducible factor-1α. Moreover, the serum also played an important role in this dedifferentiation. These findings challenge the traditional glioma cell heterogeneity model, cell division model and glioma malignancy development model. Our study also highlights the mechanism of GBM recurrence and the importance of anti-hypoxia therapy. In addition to GSCs, residual differentiated tumor cells also substantially contribute to treatment resistance and the rapid, high recurrence of GBM.

HIF1α regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels

“…There is no doubt that the enhanced expression of CD133 may be due to the proliferation of CD133 + cells that exist in the unsorted cells; however, another possibility exists that these enhanced CD133 cells originate from differentiated cells through dedifferentiation. Actually, this phenomenon has been proved by our team recently, in this study we found cancer stem cells, including glioma, hepatom and lung cancer, can be induced through dedifferentiation in hypoxia 30 , 31 . In contrast, as an effective way to alleviate a hypoxic environment, hyperoxia promotes the sensitivity of glioma cells to TMZ by decreasing the expression of MGMT, ABCG2 and Ki67 and inducing a higher cell apoptosis rate, resulting in an extended survival time for glioma patients 15 , 16 , 18 , 19 , 32 .…”

The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis

“…Prolonged hypoxia triggers the expression of CA-IX (21,22) and forms the immunohistochemically visualized regions of hypoxia. While in the center of hypoxia, due to the conditions of oxygen deficiency, several biomarkers are only expressed very low in the fringe, cells that directly border on hypoxic regions acquire resistance factors (10,11) and form stem cell and resistance regions. They gain resilience due to a more stable cell structure (intermediary filaments, e.g., GFAP, nestin, and vimentin), due to the improvement of coping strategies against stress (ALDH1), due to stabilization of the cell milieu (CA-IX) (23) and as a result of an increased migration capability.…”

“…From recently published data we know that hypoxia is an inductor of resistance factors in tumor cells and neoplastic tissue (10)(11)(12)(13). Regions of hypoxia (HReg) form our cluster 2.…”

Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development

“…Hypoxia has also been shown to promote dedifferentiation of mature glioma cells into stem-like glioma stem cells (GSCs). Hypoxia induced single differentiated CD133-/CD15-/NESTIN-glioma cells into viable neurospheres through elevated expression of critical genes including SOX-2, OCT-4, KLF-4, NANOG, CD133, CD15, NESTIN and ABCG2 [54]. Interestingly, hypoxia induced CSC enrichment also resulted in increased tumourgenicity and mortality in vivo.…”