**2. Types of stress on glioma and their clinical implications**

Internal stresses such as hypoxia, acidity, oxidative stress, and nutrient deprivation already exist within the cellular environment of tumors while external stressors like radiation treatment and genotoxic chemotherapy only worsen the internal factors. Encountering these stresses affects the process of carcinogenesis. Gliomas, especially GBM, are highly transformed tumors that react to stresses differently than less transformed cancers. Common markers of stress will be discussed along with their roles in induction of energy conservation and cell survival in glioma. Redistribution of energy resources towards survival pathways and away from energy-consuming processes is common.

Cellular stress can cause damage and mutations to numerous proteins, nucleic acid strands, and other macromolecules. The body has an innate reaction called the cellular stress response (CSR) to such damage. In the case of glioma and other cancers, the tumor is able to highjack the body's own machinery in order to help the cancerous cells survive usually by taking advantage of intrinsic or stress-related mutations. Thus, at times, stress may only further the growth and survival of tumor cells.

While the type of stress may vary, a common feature of many stresses is something referred to as the oxidative burst characterized by generation of oxidative stress and redox potential

Impact of Metabolic and Therapeutic Stresses on Glioma Progression and Therapy 25

Environmental and metabolic stress occurs during tumor growth and progression. As cancer cells divide, they take up more space. Normal cells would stop growing through contact inhibition, but malignant cells overcome the signals to inhibit growth and continue to divide. As the tumor expands, it continually outgrows its blood supply. Tumors larger than 1 mm in diameter can no longer subsist on passive diffusion of nutrients (Gimbrone, 1973). The glioma cells, thus, go through periods of severe nutrient deprivation and hypoxia until enough tumor cells are able to signal new blood vessel formation or neoangiogenesis. Even after angiogenesis, cells are still subject to stress as the new vessels are prone to collapse due to their abnormal state and harsh surrounding conditions (Vajkoczy & Menger, 2004). During this time, cancer cells must adapt to survive in conditions and intermittent periods of limited amino acids, salts, and oxygen. Some researches indicate that this is when cancer cells start to rely on glycolysis, which continues even after oxygen is available, a phenomenon known as the Warburg effect. This contributes to the high metabolic demand of proliferating tumor cells and is a relatively inefficient method of producing energy (Warburg, 1956). Therefore, the cells are put under enormous stress just to keep up with energy production needs and are subjected to further metabolic stress when nutrients

The metabolic demands of the glioma cells are partially responsible for the increased acidity or pH imbalance found in many tumors. Human brain tumors measured with electrodes had a mean pH of 6.8, with measurements as low as 5.9; the normal pH for the human brain is ~7.1 (Vaupel et al., 1989). Such pH imbalance is even found in well vascularized areas of gliomas, thus indicating that tumor cells reside within a highly acidic environment even when oxygen is present. It was originally hypothesized that that hypoxia caused the acid buildup, but these new findings mean that hypoxia and acidity are not always linked. The increased energy metabolism of the glioma cells produce hydrogen ions and metabolites like lactic acid and carbonic acid. All these products are actively pumped out of the cell through proton exchangers and other transporters (Chiche et al., 2010). In cases with decreased perfusion, poor circulation contributes to the buildup of an acidic extracellular environment. As the tumor grows, the extracellular environment strives to slow down the progress of the cancer. Growth inhibition signals are sent that can either activate or deactivate cellular receptors depending on the need. Cancer cells survive by undergoing mutations in receptors like EGFR and PDGFR, changes that either stop the signaling cascades or rewire the signaling pathways to actually promote cancer cell growth. In this way, cellular proliferation

is dissociated from nutrient availability by stress selection of surviving cells.

oxygen but leads to oxidative stress as well.

Hypoxia can play a major role in glioma development, with oxygen deprivation actually being necessary for tumor progression through alteration of gene expression, genomic instability, apoptotic dysregulation, and neoangiogenesis. In glioma, hypoxia is believed to be a key player due to the evidence of tumor necrosis in highly malignant forms like glioblastoma multiforme (GBM) (Brat & Meir, 2001). Brain tumors smaller than the previously stated 1 mm cutoff are found to be highly hypoxic and ill-perfused (Li et al. 2007). The oxygen deprivation is actually responsible for the growth of elaborate microvascular networks that indicate tumor progression in GBM. Even though larger GBM tumors are more vascularized, the blood vessels present are inefficient, and parts of the tumor environment remain hypoxic (Vajkoczy & Menger, 2004). Further transformation of the tumor cells occurs as reactive oxygen species (ROSs) increase during this time due to production by the mitochondria (Lui et al., 2008). Thus, hypoxia not only deprives cells of

become unavailable.

changes. Reactive oxygen species (ROSs) can be produced from activation of NADPH oxidase or other ceullar oxidases in the cell's various membranes. Stressor-specific responses, on the other hand, may be induced differentially depending on the type, severity, and duration of the stress. The following sections will cover these stresses and the resulting responses by normal cells and cancerous glioma cells.
