ADVERTISEMENT

Hypoxic Niche, Stemness And Differentiation State In Glioblastomas

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:

ADVERTISEMENT
  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, otherĀ 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.

ADVERTISEMENT

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.

ADVERTISEMENT

Comments

READ THIS NEXT

Toward A 3D Metamorphic Touchpad

Published by Shantonu Biswas California NanoSystems Institute, University of California, Santa Barbara These findings are described in the article entitled […]

Coral Color: The Science Behind Coral

The color coral gets its unique coloration from the organisms that live within the coral, forming a symbiotic relationship with […]

Increased PPAR-Ī³ Expression To Help Regulate Obesity And Overweight

Accordingly to the World Health Organization (WHO), almost 2 billion adults were overweight in 2016. Of these, over 650 million […]

Wind-blown Sand Dune Accumulation At The End Of A Dry Phase

More than one-third of the Earth’s land surface is arid and semiarid lands with meager rainfall. At present, more than […]

Combination Of Life Cycle Thinking And Environmental Communication To Improve Our Pro-Environmental Behavior

Municipal solid waste (MSW) is the waste that we produce in our home. It is mainly composed of putrescible and […]

Citrine: Characteristics And Properties

Citrine is an incredible mineral variety of quartz with interesting properties and characteristics.Ā Citrine is a quartz characterized by its yellow […]

Injuries And Concussions Of Young Athletes Playing In Recreational Leagues

Do young children athletes playing sports in recreational leagues get injured or have concussions? Many people may think that young […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?