Study Suggests Ovarian Cancer Cells Can Alter Surroundings to Promote Self-Preservation, Chemotherapy Resistance
Compelling new scientific evidence suggests cancer cells can trigger changes in their immediate surroundings that promote self-preservation. Collagen VI, a protein produced by ovarian cancer cells, appears to help these cells alter their microenvironment so they are more resistant to chemotherapeutic drugs commonly used to treat the disease, according to investigators at the National Institute on Aging (NIA) Intramural Research Program and colleagues at other research centers.
"It has been known for some time that the microenvironment of cancer cells can affect the response of these cells to chemotherapy. But our data show that cancer cells can remodel their surroundings to make themselves more resistant to chemotherapy. This is quite an intriguing concept," says Patrice Morin, Ph.D., an investigator specializing in cancer molecular genetics in the NIA's Laboratory of Cellular and Molecular Biology. The findings* are reported in the April 2003 issue of Cancer Cell.
Blocking the production or the effects of collagen VI in ovarian cancer cells could increase the effectiveness of chemotherapy treatments and improve survival rates for this cancer, which occurs most frequently in women older than 50 who have gone through menopause, Dr. Morin says.
"Drug resistance is a major problem in cancer treatment in general, and in ovarian cancer in particular," he says. "We were interested in finding out the mechanisms of resistance. Just how is it that cancer cells become resistant to chemotherapy?"
To find out, Dr. Morin and his colleagues used serial analysis gene expression (SAGE) technology to examine more than 15,000 common genes in two ovarian cancer cell lines with differing degrees of resistance to chemotherapy. SAGE is a new tool to evaluate the genes
expressed in cells of interest. After analyzing their findings, the investigator found only 16 genes that were differentially up or down regulated in the cell line that was most resistant to chemotherapy. Of these, they focused their attention on a gene called COL6A3, which expresses the collagen VI protein. Previous studies had shown that collagen is upregulated in advanced ovarian cancers. In subsequent experiments, the investigators found ovarian cancer cell lines grown in culture dishes coated with collagen VI were significantly more resistant to Cisplatin, a drug commonly used to treat ovarian cancer, than were similar cell lines grown in untreated culture dishes.
All cells produce collagens and other proteins that help build the extracellular matrix, an underlying structure in the microenvironment that regulates cellular growth. But in Dr. Morin's study, collagen VI did something unexpected as it was produced and secreted by ovarian cancer cells. It caused changes in the extracellular matrix that made the environment more favorable for the growth and survival of these cancer cells, and which made them less susceptible to chemotherapy. Collagen VI is also known to interact with specific receptors on the surface of ovarian cancer cells. Dr. Morin and his colleagues are investigating how these interactions promote resistance to chemotherapy.
Each year, about 23,000 American women are diagnosed with ovarian cancer and 14,000 die of this disease. The vast majority of these women die with chemotherapy resistant tumors. "Understanding how these cancer cells develop resistance to chemotherapy and finding therapeutic interventions to overcome this resistance are paramount," Dr. Morin says.
The National Institute on Aging is one of 27 Institutes and Centers that
constitute the National Institutes of Health. The NIA leads Federal
efforts to support and conduct basic, clinical, epidemiological,
and social research on aging and the special needs of older people.
Press releases, fact sheets, and other materials about aging and
aging research can be viewed at the NIA's general information Web
site, www.nia.nih.gov. Investigators
from the University of California, San Francisco, University of
Michigan Medical School, The Johns Hopkins Medical Institutions,
and the National Human Genome Research Institute, a part of the
NIH, contributed to this study.