Cancer Physiology Project
Accumulating evidence suggests that the conditions surrounding the cancer cells in growing solid tumors are significantly different from those in the experimental cell culture system, i.e., the oxygen and nutrient supply is much lower in vivo due to insufficient blood supply. It is highly probable that cancer cells behave in a totally different manner in such a physiological microenvironment. Describing the authentic physiology of cancer cells may bring enormous benefit for innovation and formulation of rational strategies for cancer treatment.
Autophagy and Cancer
The manner in which cancer cells obtain
nutrients when external supply is limited remains an enigma. One possible solution is that the cells digest their own components and obtain amino acids as an alternative energy source. Autophagy is a conserved catabolic process by which cells self-digest their organelles and is claimed to be a response to metabolic stresses such as nutrient depletion. In cultured colorectal cancer cells that present “austerity”, which is a resistance to nutrient starvation, autophagy was highly activated under nutrient-deprived conditions. In addition, inhibition of autophagy led to cell death in a nutrient depletion-specific manner. Thus, autophagy plays a protective role in the survival of cancer cells. Evaluating autophagy in clinical samples has been hampered by the lack of an appropriate surrogate marker. The levels of the LC3 protein are dynamically altered during autophagy. Immunohistochemistry using an anti-LC3 antibody revealed massive and specific accumulation of the LC3 protein in surgically resected colorectal cancer specimens, suggesting the contribution of autophagy to tumorigenesis. A new insight into autophagy in cancer biology will be obtained by using this technique (91).
Development of Anti-austeric drugs
Targeting austerity is a potential new strategy for cancer treatment. Several compounds such as kigamicin D and arctigenin have been identified as candidate anti-austeric drugs. Exploring such candidate compounds is being continued. A series of plant extracts were applied to an in vitro screening system. The chloroform extract of the rhizomes of Boesenbergia pandurata demonstrated arked preferential toxicity against pancreatic cancer-derived PANC-1 cells in a nutrient-derived medium (92).
Involvement of c-Maf and ALDH2 in Tumorigenesis
The transcription factor c-Maf transactivates various genes including ARK5, a member of the AMPK-related kinases regulating austerity. Recent studies have revealed that c-Maf was overexpressed in multiple myeloma cells. Overexpression of c-Maf was also observed specifically in angioimmunoblastic T-cell lymphomas (93). Alcohol consumption had a positive association with the risk of lung cancer. Furthermore, the risk was increased among the individuals having the variant ALDH2 allele, suggesting that acetaldehyde plays an important role in alcohol-related carcinogenesis. (94).
● K. Tsuchihara ●
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