Like a siren song, breast cancer secretes growth factors to attract stem cells then uses those cells – which normally promote healing – to help it survive, researchers have found.
In the laboratory, the researchers have documented secretion of growth factors FGF2 and VEGF by breast cancer cells, seen these factors bind to receptors on stem cells then watched stem cells migrate toward the cancer. When they took the growth factors away, the deadly migration decreased.
“These stem cells are there to make normal tissue; they make fat, cartilage, bone,” says Dr. Adam Perry, general surgery resident at the Medical College of Georgia. “But if you have a tumor, it will in a sense mimic some tissue type to get the cells to come and help form the environment that is called the tumor stroma that it needs to get beyond a certain size. That’s really when cancer becomes clinically problematic.”
Knowing how tumors attract the stem cells they need to thrive opens up new avenues for earlier detection, better staging and more targeted therapies, he says.
Dr. Perry’s work on this fatal attraction between cancer and adult bone marrow stem cells earned him the Peter J. Gingrass, M.D. Memorial Award for the best paper presented by a medical student or non-plastic surgery resident during the recent 50th anniversary meeting of the Plastic Surgery Research Council.
“When you have a growing tumor, the tumor cells cannot stand alone,” says Dr. Edmond Ritter, MCG plastic surgeon and senior co-investigator. “Tumors have specific colon cancer or breast cancer or melanoma cells, but they also have to have supporting framework which includes fibroblasts as well as blood vessels.”
Normally, FGF2 makes connective tissue and VEGF makes blood vessels. It was known that tumors contain these growth factors as well as others and that they utilize stem cells to help build the infrastructure they need. “We wanted to figure out what attracts these stem cells,” says Dr. Perry. “What makes them move?”
“You need blood vessels. You need other tissue that forms basically a home or a nest for the tumor,” says Dr. Erhard Bieberich, MCG biochemist and senior investigator. “Without that, you don’t get metastasis. Without the activity of those stem cells, metastasis would only grow to a particular size but it would not be life-threatening. But once the body response kicks in and accepts the metastasis as some sort of useful tissue, it really gets dangerous.”
The MCG researchers hypothesized that growth factors secreted by tumors cells might play a role in this acceptance.
Dr. Bao-Ling Adam, a cancer researcher and proteomics expert, helped measure levels of FGF2 and VEGF – both proteins – using a high-tech approach that enables evaluation of hundreds of proteins at one time.
Cells need protein to survive and cells normally keep some proteins they make and shed others, Dr. Adam says. Much as a blood test can show what proteins are being secreted in the body, the researchers looked in the cell culture media where the cancer cells resided to see what proteins were being secreted.
“We wanted to see what kind of molecules are released in the media and then what molecules attract stem cells,” says Dr. Adam. They are still working to identify other molecules that were secreted, but FGF2 and VEGF were definite standouts.
“In the case of breast cancer, FGF2 and VEGF meet the criteria as candidate molecules and we believe they have an important role but are not the only answer as to why stem cells migrate,” says Dr. Ritter, who specializes in reconstruction following mastectomy.
The researchers say different kinds of tumors likely send out different growth factors to lure stem cells. In fact, they’ve already shown that melanoma also uses VEGF but not FGF2. “You don’t want to treat every tumor alike,” says Dr. Ritter.
They believe knowing the factors that help lead stem cells astray is an important first step in stopping the deadly attraction. “The first generation of chemotherapy was more targeting the cell division of cancer,” says Dr. Bieberich. “Now we are entering a new phase where we are targeting more the communication pathways.” Possibilities include using antibodies or other small molecules to block growth factor receptors or even turning the tables on cancer by arming stem cells with a mechanism to kill the cancer once they connect, he says.
Dr. Perry has seen the need for options other than chemotherapy, radiation therapy or surgery in his relatively short professional life. “What we are doing now is looking at more precise, specific ways to treat cancer on cellular level. This requires an immense understanding of tumor biology and what is going on. We are trying to chip away at that puzzle.”
Dr. Perry is just completing a year of research in the laboratories of Drs. Bieberich and Adam. He plans to pursue a plastic surgery fellowship after completing his surgery residency.
A significant part of the initial work for these studies was conducted by Kathryn Tucciarone, who worked as a research assistant in Dr. Bieberich’s lab. Dr. Jack Yu, chief of the Section of Plastic and Reconstructive Surgery, and Dr. Thomas N. Wang, surgical oncologist, also supported the studies.
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