How does the tumor microenvironment influence the resistance to targeted therapies in glioblastoma?
Hello Tajinder Kumar Saini
In glioblastoma, the tumor microenvironment plays a key role in tumor progression by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes and other immune effector cell types that contribute to tumor proliferation and growth. In addition to low immunogenicity, the blood–brain barrier also restricts immune infiltration.
The hypoxic environment influences resistance to therapies in glioblastoma. Tumor cells respond to hypoxic conditions by upregulating HIFs which in turn activate gene expression of downstream targets needed for cell survival. The dimerization of HIF-1α and HIF-1β leads to the upregulation of proangiogenic genes, such as VEGF, fibroblast growth factor, and several others leading to an increase in angiogenesis, invasiveness, and tumor migration.
Another factor to consider is the acidic environment in the tumor microenvironment which can facilitate several pro-tumorigenic processes including proliferation, migration, and angiogenesis. Also, given that such an acidic environment is a potential threat to cancer cells, to counter this, malignant cells activate protective mechanisms related to tumor-associated acidosis that can further enhance the ability of the cells to survive such harsh environmental conditions.
As already mentioned above, the immune suppressive microenvironment in glioblastoma has a role in generating treatment resistance with respect to targeted therapies and other therapeutic immune responses. Microglia and glioma associated macrophages are the most abundant immune cells in the microenvironment of most primary gliomas. However, these are generally immunosuppressive in the glioma microenvironment. Glioma associated macrophages can produce anti-inflammatory cytokines, tumor-promoting factors, promote angiogenesis, disrupt metabolism, and activate immune checkpoints. The myeloid-derived suppressive cells, which are derivatives of monocytic or granulocytic cells, are also detected in the glioma tumor microenvironment. These cells suppress tumor-specific effector T cells in a manner similar to that of glioma associated macrophages. The CD8+ and CD4+T cells found in glioblastoma are often dysfunctional because of senescence, tolerance, anergy, or exhaustion. Therefore, most gliomas are intrinsically poorly immunogenic causing an obstacle to targeted therapy.
You may want to refer to the article attached below for more information.
Article Tumor Microenvironment in Glioblastoma: Current and Emerging Concepts
Best.
Hypoxia-activated genes specifically make the tumor microenvironment more acidic. The acidic tumor microenvironment can facilitate EMT, ECM degradation, and cancer cell migration. In addition to this process, the major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis.
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