山形大学医学部 腫瘍分子医科学講座

Sitemap



Resarch

The Department aims to elucidate the molecular basis underlying fundamental processes in cancer cell biology and translate the results into novel therapeutic strategies against cancer. Research projects on-going in our laboratory include:

1. Non-apoptotic programmed cell death (PCD)

In the late 90’s0early 00’s when apoptosis was still "the synonym" of PCD, we made pioneering observations that a cell death program -distinct from apoptosis both in terms of morphology and regulatory mechanism (i.e., non-apoptotic)  plays a role in the elimination of cancer cells with deregulated oncogene (ras) activation (Chi et al., 1999; Kitanaka et al., 2002 = selected as a RESEARCH HIGHLIGHT in the April issue of Nature Reviews Cancer, 2002). Our discoveries contributed to the dissemination of the novel idea that non-apoptotic PCDs do exist and have important patho-physiological roles, which has now come to be widely accepted. Presently, dissection of the molecular mechanism involved in the regulation of ras-driven non-apoptotic PCD is in progress in our laboratory. To date, we have successfully identified key regulatory molecules of the non-apoptotic PCD, which could become potential targets for the treatment of cancers that are usually resistant against apoptotic PCD.

2. Novel role of energy metabolism in the regulation of programmed cancer cell death

Cancer cells have a propensity to produce energy (=ATP) in an anaerobic manner even in the presence of ample oxygen, which is termed Warburg effect. Warburg effect is thus a common phenotype of cancer cells and forms a basis for cancer detection by 18-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) scans. However, why cancer cells choose to rely heavily on such an inefficient way of energy production (~1/20 efficient compared to aerobic energy production) has remained a mystery for nearly 80 years since the discovery of Warburg effect. We have recently discovered that the aerobic energy metabolism, but not the anaerobic one, plays a pivotal role in the activation of Bax and Bak essential for mitochondria-mediated cellular suicide (Tomiyama et al., 2006 = selected as a RESEARCH HIGHLIGHT in the December issue of Nature Reviews Cancer, 2006). Since cancer cells, unlike normal cells, are continuously exposed to various external and internal stimuli that cause them to commit suicide, cancer cells need to actively avoid suicide to survive and grow. Thus, with our discovery, the “seemingly absurd energy metabolism” of cancer cells can now be viewed as a “crafty strategy” to avoid suicide commitment at the cost of energy production efficiency. Another important implication of our findings in light of cancer therapeutics is that, if we can shift the metabolism of cancer cells from anaerobic to aerobic, then we can sensitize them to conventional cancer therapies, which often depend on the mitochondria-mediated suicide mechanism for cell killing. We have recently identified a natural compound that promotes aerobic metabolism of glioblastoma (GBM) cells. The possibility of combination therapies involving the use of this newly identified metabolic drug and chemotherapeutic agents against GBM (e.g., temozolomide) is now being explored.

3. The maintenance mechanism of cancer stem cells

The cancer stem cell hypothesis holds that tumors are comprised of a rare population of cancer “stem” cells that retain the ability to give rise to a new tumor that recapitulates the original tumor and of the remaining majority of “non-stem” cancer cells with limited potential to proliferate. Because the presumptive cancer stem cells in general have higher resistance against radiation and chemotherapy than non-stem cancer cells, they are now regarded as potential seeds of recurrence after cancer treatment. As such, cancer stem cells are rapidly emerging as an intense focus of cancer research. According to the cancer stem cell hypothesis, it is expected that, if we know the key molecular determinants that distinguish cancer stem cells from non-stem cells, then we would be able to identify drugs that target those key molecules and turn cancer stem cells into non-stem cells. Such drugs would not be effective as a single agent but would greatly improve progression-free and overall survival by preventing recurrence when combined with conventional cancer therapies. Presently, studies are ongoing in our laboratory to elucidate the molecular mechanism by which GBM stem cells maintain their “stemness”. Key molecules essential for the stemness of GBM stem cells as well as pharmacological agents targeting those molecules are being identified in our laboratory. Therapeutic potential of these drugs against GBM is to be investigated in the near future.
  • 山形大学医学部
  • 山形大学医学部附属病院

PageTop


Copyright 2013 Yamagata University Faculty of Medicine.