Hypoxic Niche, Stemness And Differentiation State In Glioblastomas

Photomicrographs of glioblastoma cells under normal conditions (control), under hypoxia and under reoxygenation to show cell morphology.

Glioblastomas, or GBMs, are the most aggressive CNS tumors, they are highly infiltrative, proliferative and heterogeneous. The current therapy involves surgical resection plus radio and chemotherapy and the life expectancy is around fifteen months. The standard drug used for chemotherapy is temozolomide.

GBM is often characterized by rapid growth and invasion into surrounding normal brain tissue. GBM origins are divided into 3 hypotheses:

  1. Differentiated cells suffer mutations in tumor suppressor genes and oncogenes that induce dedifferentiation and tumor development;
  2. Neural progenitor cells suffer mutations and acquire stem properties;
  3. Adult neural stem cells suffer mutations and those transform the stem cell and initiate tumor development. This last hypothesis originated the term cancer stem cells or tumor stem cell.

Because of these different origins, the tumor cells will have different genetic types. GBMs can be divided into 4 genetic classifications such as: classical, mesenchymal, neural and proneural. This explains the aggressiveness of GBMs because a single tumor can present more than one of those genetic types. It is as if we are dealing with one cancer that has 4 different cancers inside with different genetic and molecular characteristics that sometimes results in different morphologies.

Furthermore, other reasons contribute for the therapy resistance of glioblastomas, as the difficulty of drugs to reach pharmacologically effective concentrations in the tumor mass, the blood-brain barrier hinders the access of most antitumor drugs to the tumor site, and the heterogeneity may be a therapeutic challenge because the cells may respond differently to therapy. Also, since they are invasive tumors, it is not possible to perform the complete surgical resection.

So the question is: how to study such a heterogeneous tumor? And how to design effective therapies?

Some studies identified a population of stem cells with special properties, the cancer stem cells (CSC), which have the ability of self-renewal, to differentiate in several types of tumor cells and to sustain tumor growth in vivo. From the clinical point of view, they are important due to their elevated resistance to radio and chemotherapy. This explains the inefficacy of current therapy, which is limited to conventional approaches that aim to eliminate the neoplastic population in a bulk, without considering the remaining cells, such as CSC, which can regenerate the tumor.

Moreover, glioblastomas are capable of promoting tissue angiogenesis. However, this mechanism of formation of new vessels does not completely supply the bulk of neoplastic cells with nutrients and oxygen, which favors the formation of hypoxic areas. This phenomenon is common in solid tumors, where O2 concentration in the tumor mass varies from 2.5 to 5.3% and can reach below 0.1% in necrotic regions, characterizing a hypoxic microenvironment. Hypoxic microenvironments contribute to tumor progression through activation of adaptive transcriptional programs that promote cell survival, motility and angiogenesis. Furthermore, studies show that hypoxia induces dedifferentiation of mature tumor cells to CSC.

To investigate the role of hypoxia on glioma cells, we simulated the hypoxic tumor microenvironment in vitro and characterized the features of hypoxia in the malignant glioma. The absence of serum in conjunction with hypoxia seems to promote a favorable environment for CSC proliferation and/or cell dedifferentiation. Studies show that hypoxia induces dedifferentiation of differentiated glioma cells, causing them to acquire stemness. Moreover, neural precursors maintain undifferentiated phenotypes in low O2 concentrations, while higher O2 concentrations promote cellular differentiation.

Furthermore, we analyzed the reoxygenation period. During this process, we observed an increase in differentiation markers, which is common in the periphery of in vivo tumors.

Studies show that the tumor hypoxic core of glioblastoma in vivo shows resistance to temozolomide. Therefore, mimicking the hypoxic microenvironment may contribute to the study of new antiglioma drugs. In brief, we changed the environmental conditions of tumor cells and characterized the in vitro hypoxic microenvironment associated with GBM tumors, therefore contributing to new insights for the development of therapeutics for resistant glioblastoma.

These findings are described in the article entitled Hypoxic and Reoxygenated Microenvironment: Stemness and Differentiation State in Glioblastoma, published in the journal Molecular Neurobiology. This work was led by Mariana Maier Gaelzer from the Federal University of Rio Grande do Sul.

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