Houston’s University of Texas MD Anderson Cancer Center says that if you want to understand why cancer cells metastasize — think of Sparta, the Greek city-state that as a political and military power spanned the cusp of the bronze and early iron ages from about 650 BC to the Roman conquest in 146 BC. Spartan warriors were fed a special diet that better prepared them for the demands of battle on distant fields.
MD Anderson scientists say cancer cells that metastasize may do the same thing, according to a new study that has revealed previously unknown differences in cancer cells that continue to grow at the original tumor site, and those that travel to invade other organs. Given that a cancer cells’ relentless ability to metastasize is the primary cause of cancer-related death, understanding how they successfully migrate could be lifesaving.
Researchers at MD Anderson and affiliated institutions in the U.S., Germany, and Brazil have found that cancer cells traveling to other sites have different energy needs compared with their stay-at-home siblings which continue to proliferate at the original tumor site. The study results are published in the Sept. 21 online edition of the journal Nature Cell Biology.
The scientists suggest that the reason may lie with the protein, PGC-1, a type of transcription co-activator crucial to regulation of cellular metabolism. They say PGC-1 appears to play a role in how cancer cells are able to acquire unique energy sources that allow them to travel and spread cancer in the body.
The research article, entitled “PGC-1 mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis” (Published online 21 September 2014 Nature Cell Biology doi:10.1038/ncb3039), is coauthored by Valerie S. LeBleu and Raghu Kalluri of the Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, also affiliated with Joyce T. O’Connell at the Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center in Boston, Massachusetts; Karina N. Gonzalez Herrera and Marcia C. Haigis of the Department of Cell Biology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts; Harriet Wikman and Klaus Pantel of the Department of Tumor Biology, University Medical Center Hamburg-Eppendorf in Hamburg, Germany; Fernanda Machado de Carvalho, Aline Damascena, Ludmilla Thome Domingos Chinen and Rafael M. Rocha of the International Research Center, A. C. Camargo Cancer Center at Sao Paulo, Brazil; and John M. Asara of the Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Harvard Medical School Department of Medicine at Boston, Massachusetts.
The coauthors note that cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate cellular building blocks required for tumor growth. However, they say the specific bioenergetic profile of invasive and metastatic cancer cells is unknown.
In their paper, the researchers report that migratory/invasive cancer cells specifically favor mitochondrial respiration and increased ATP production, and that invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha ( PPARGC1A, also known as PGC-1) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate.
The coauthors report that clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1 expression in invasive cancer cells and formation of distant metastases. They observe that silencing of PGC-1 in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1 are also essential for functional motility of cancer cells and metastasis.
“New therapy strategies are beginning to focus on the unique vulnerabilities of cancer cell metabolism. Determining the metabolic requirements of invasive cancer cells could be of therapeutic value,” says Valerie LeBleu, Ph.D. , an assistant professor of cancer biology at MD Anderson and lead author of the Nature Cell Biology paper in a MD Anderson release. “We found that invading cancer cells rely on mitochondria during their transition to other cancer sites.”
Dr. LeBleu’s research program bridges cancer biology with organ fibrosis, with an emphasis in understanding the underlying molecular mechanisms regulating the pathological remodeling of the affected organ. Her research efforts focus on elucidating the functional contribution of pathological stroma in cancer initiation, solid tumor growth, and metastatic dissemination. Her lab makes extensive use of and continues to develop novel genetically engineered mouse models of lung and breast cancer as well as organ fibrosis including lung and kidney fibrosis. Ongoing projects include the study of lung neoplasia and metastatic growth and study of the metabolic cooperation of stroma and cancer cells in breast and lung cancer progression.
Cancer cells use PGC-1 to stimulate the growth of new mitochondria, the cell s power plants that generate ATP, an energy currency used by cells to grow. Metastasizing cells also rely on PGC-1 for a process known as oxidative phosphorylation that boosts ATP during the cell s journey to other sites. If mitochondria is the kitchen, then PGC-1 is the chef, ATP the entre and oxidative phosphorylation a key ingredient. This overall process, mitochondria respiration, allows some cancer cells to harness the required energy to survive the hostile journey through tumor and normal issue, blood vessels, and entry into new organs.
In other words, returning to the Spartan analogy, some cancer cells are programmed to eat at home, while others have a special diet that allows them to travel to other sites. If there was a therapeutic way to stop the migrating cells from packing a lunch ahead of time, it could potentially halt their journey, and the MD Anderson scientists say suppressing PGC-1 appears to accomplish this.
“The most dangerous cancer cells are the ones that can efficiently move and find a new home, says Raghu Kalluri, M.D., Ph.D., chair of cancer biology and an investigator on the study, which as noted above revealed a strong correlation between PGC-1 expression in invasive cancer cells and the formation of distant metastases in breast cancer patients.
The study was funded by the Cancer Prevention and Research Institute of Texas, MD Anderson Cancer Center, the Department of Defense Cancer Research Predoctoral Traineeship Award (W81XWH-09-1-0008). Dr. Kalluri is also funded by the National Institutes of Health (CA 125550, CA 1555370, CA 151925, DK081576, DK055001, CA12096405, and CA00651646).
University of Texas, MD Anderson Cancer Center
Nature Cell Biology
University of Texas, MD Anderson Cancer Center