The identification of comprising cells and composition of microenvironment, which is the result of many years of work in many research labs across the globe, has made it possible to see just the tip of iceberg. The dynamic and fluid nature of microenvironment, with its tumor agonistic and antagonistic cells at one end, and its intricate communication with tumor mass, is leaving us with many unanswered questions, both conceptually and functionally. Tumor associated macrophages, tumor associated fibroblasts, B and T regulatory cells, angiogenesis factors and many other cellular, and humeral factors, comprise elements of tumor microenvironment eco-system. Tissue resident macrophages, originating from bone marrow are among the tumor antagonists. However, the most puzzling of all are tissue resident macrophages that originate from the yolk sac of embryo and dispersed in all organs.

Originally identified for its involvement in phosphorylating glycogen synthase and regulating glucose metabolism in response to insulin, glycogen synthase kinase-3 (GSK-3) has since been recognized as a versatile serine/threonine kinase with diverse functions [1,2]. Extensive research has demonstrated that GSK-3 phosphorylates over 100 protein substrates where it intersects numerous signaling pathways. While it was initially implicated in the regulation of glucose metabolism, subsequent investigations revealed an impact of GSK-3 in cellular processes beyond glycogen synthase phosphorylation and glycogen metabolism [3].

The formation of new blood vessels, or angiogenesis, is a hallmark of cancer and one of the most important conditions for tumor growth. Vascular endothelial growth factor (VEGF) is one of the most important factors in angiogenesis. Increased VEGF expression has been associated to rapid cancer progression and poor prognosis. 

Brain tumors, especially malignant gliomas and metastases, continue to pose serious clinical challenges due to their complex biology and limited treatment options. The traditional research paradigm mainly focuses on the tumor cells themselves and their interaction with the immune microenvironment, while the critical role of the nervous system (including neurons, glial cells, neurotransmitters/modulators, and nerve fibers) in the pathological process of tumors has been underestimated for a long time.