Stem Cell Microenvironments and Beyond by Alexander Birbrair

Author:Alexander Birbrair
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

7.4.2 Hypoxic Niche

In healthy brain tissue, the normal physiological oxygen concentration ranges between 12.5 and 2.5%. GBM tissue however shows regions of mild hypoxia (2.5–0.5%) and severe hypoxia (0.5–0.1%) (Evans et al. 2004). It is hypothesized that the oxygen tension gradient within a tumor niche plays a vital role in differentiation of cells. The cells present in the periphery of tumor masses are thought to exhibit low proliferation rate, low levels of HIF1α and increased angiogenesis. The cells present at the tumor core are thought to exist in near anoxic conditions with very low proliferation rates and high levels of HIF1α. Cells present in the intermediate region of tumors are thought to high proliferation rate, form neurospheres in hypoxic conditions and show increased levels of expression of VEGF, Glut1 and carbonic anhydrase IX (CAIX) (Pistollato et al. 2010). Therefore, the presence of intratumoral hypoxia promotes the existence of a pool of stem-like cancer cells at the core of the tumor which are often resistant to radio- and chemo- therapies.

The importance of hypoxia in maintaining the differentiation state and proliferation of normal stem cells within their niches and its mechanism is well established. Within the bone marrow, hematopoietic stem cells (HSCs) migrate to hypoxic niches where they are maintained in a state of quiescence by the hypoxia induced protein, osteopontin (Stier et al. 2005). Severe hypoxia also prevents the differentiation of NSCs and embryonic stem cells without affecting their proliferation while also improving the generation of induced pluripotent stem cells (iPSCs) (Mathieu et al. 2014).

Neovascularization within GBM tissue often results in the formation of disorganized, chaotic and highly torturous blood vessels which are unable to effectively supply the entire tumor tissue with oxygen and nutrients. The lack of uniform oxygenation and the high proliferative rate of tumor cells results in the formation of regions of pseudopalisading necrosis that develop in order to protect the surrounding normal tissue from effects of hypoxia (Brat et al. 2004). Hypoxia and the activation of hypoxia response genes are thought to play a vital role in GBM progression, proliferation, aggressiveness and resistance to therapy. This was directly demonstrated in a recent multicenter trial that found hypoxia levels in GBM patients demonstrated by 18F–FMISO PET/CT correlated with worse prognosis (Gerstner et al. 2016).

The effect of hypoxia on cells is mediated through intracellular family of proteins called hypoxia inducible factors (HIFs) which form transcriptional complexes consisting of HIF-β subunit (ARNT- aryl hydrocarbon nuclear translocator) which is constitutively expressed and oxygen regulated HIF-α subunits which belong to the basic helix-loop-helix-Per-Arnt-Sims (PAS) family of transcriptional activators . HIF1α (ubiquitously expressed), HIF 2α and HIF3α (tissue specific expression) are the three mammalian HIF-1 subunits. Even though the HIF-1α is highly transcribed and translated in normoxic conditions, it is rapidly hydroxylated on two conserved proline residues (P402 and P564) on the oxygen dependent degradation domain (ODD) by HIF specific prolyl hydroxylases PHD1, PHD2 and PHD3. Hydroxylated HIF-1α is then recognized by the von Hippel-Lindau tumor suppressor (pVHL) , a subunit of E3

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