Newswise — Cancer Research is one of the most influential cancer journals, publishing original studies, reviews and opinion pieces on preclinical, clinical, prevention and epidemiologic cancer research. It is also the most cited cancer journal in the world, so it was a great honor when the editor recently informed VCU Massey Cancer Center scientist David Gewirtz, Ph.D., that his February 2014 manuscript, “The Four Faces of Autophagy,” was the most highly cited Cancer Research review article published in 2014.

Academic research is highly collaborative. Research findings published in journals such as Cancer Research build upon the work of other published studies and offer a new basis for understanding a particular subject that informs the future work of other researchers. When scientists publish new research, they typically cite previous studies that informed their research or were related to their findings.

Gewirtz’s manuscript was a review of research that challenged the conventional understanding of a cellular process known as autophagy. Autophagy is a natural mechanism that breaks down and recycles unwanted cellular components.

Autophagy also undertakes a protective role in tumor cells when it degrades some of the cellular components in order to generate the required energy needed to stay alive in response to chemotherapy and radiation. This cytoprotective function was largely thought to be the only role autophagy plays in cancer; however, Gewirtz’s review proposes that there are actually at least four different forms of autophagy, and only one form protects the cell from external stress.

“There has been a great deal of effort to develop new therapies that suppress autophagy in order to make cancer cells more sensitive to chemotherapy and radiation. Our work suggests that this strategy is likely to be effective only in certain circumstances,” says Gewirtz, member of the Developmental Therapeutics research program at VCU Massey Cancer Center and professor of pharmacology, toxicology and medicine at the VCU School of Medicine. “As a result, we need to develop new ways to test whether or not autophagy in response to cancer treatment is cytoprotective before employing therapies designed to inhibit it.

Gewirtz’s findings have implications for virtually all forms of cancer, particularly solid tumors, which underscores the importance of his research and why it has been cited so frequently since its publication.

In his review, he described the various forms of autophagy and their functional characteristics as:

- Cytoprotective: This form is most commonly associated with resistance to chemotherapy and radiation, and it supports the concept of therapeutic inhibition of autophagy during cancer treatment.

- Cytotoxic: This form promotes cell death when triggered. This cell death may be associated with a form of cell suicide known as apoptosis. When inhibited with drugs, this form of autophagy may promote resistance to cancer therapies.

- Cytostatic: This form appears to mediate growth arrest in cancer cells and may be involved in tumor dormancy following treatment. While it is associated with a reduction in cell survival, it is different than cytoprotective autophagy in that inhibiting it is not associated with increased cell killing.

- Nonprotective: This form does not appear to influence sensitivity to therapy, yet it is still activated in cancer cells exposed to cancer therapies.While scientists can detect whether autophagy is occurring, there is currently no test that can distinguish between the various forms. The functional differences described in Gewirtz’ review are based on empirical evidence observed and reported in a multitude of studies. Additional studies attempting to further define these differences are ongoing.

Gewirtz collaborated on this research with Hisashi Harada, Ph.D., member of the Cancer Cell Signaling research program at VCU Massey Cancer Center and assistant professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry; Masoud Manjili, D.V.M., Ph.D., member of the Cancer Cell Signaling research program at Massey and associate professor of microbiology and immunology at the VCU School of Medicine; Kristoffer Valerie, Ph.D., co-leader and member of the Radiation Biology and Oncology research program at Massey and professor in the Department of Radiation Oncology at the VCU School of Medicine; Lawrence Povirk, Ph.D., member of the Radiation Biology and Oncology research program at Massey and professor of pharmacology and toxicology at the VCU School of Medicine; Andrew Yeudall, Ph.D., associate professor at the VCU Philips Institute for Oral Health Research; and Andrew Thornburn, Ph.D., from the University of Colorado.

Gewirtz’s research is supported by grants from the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH-14-1-0088 and the National Institutes of Health (RO1 CA206028-O1PQ9) and, in part, by Massey’s National Institutes of Health-National Cancer Institute Cancer Center Support Grant P30 CA016059.

Gewirtz’s review is available online at:

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W81XWH-14-1-0088; RO1 CA206028-O1PQ9; P30 CA016059; Cancer Research, April-2014