Researcher explores tumors’ survival strategy

Dr. Kouros Motamed is studying endothelial cells where they live, in the complex environment that provides, not only support and structure, but regulation and direction.

As he studies these cells that line blood vessels, this vascular biologist at the Medical College of Georgia focuses on the proteins and growth factors that regulate their normal processes, including proliferation, differentiation, migration and death.

He wants to better understand how these cells interact with their environment because there are still many unanswered questions.

But he also wants to know because tumors sometimes commandeer these cells’ ability to grow new blood vessels that bring life-sustaining nutrients and oxygen. “For most tumors to become any larger than 2 to 3 millimeters (a small fraction of an inch) in diameter, they have to recruit blood vessels,” said Dr. Motamed.

This new vessel growth, called angiogenesis, can be beneficial. An injury can throw an angiogenic switch, activating a previously quiet endothelial cell. “As a result of activation, the endothelial cell loses its contact with the matrix (the milieu cells live in), elongates and invades the surrounding, stromal tissue,” Dr. Motamed said. The cell then begins to proliferate, forming the lumen through which blood will eventually flow, and recruits supporting cell types and matrix components to form a new, functional vascular bed that is believed to accelerate wound healing.

The fact that many tumors also activate angiogenesis to survive has helped make it a hot topic in science. Dr. Motamed, who came to MCG in September from The Hope Heart Institute in Seattle, has his eye on the role of basic fibroblast growth factor in promoting angiogenesis and a protein called SPARC, which seems to have multiple roles in cancer and new blood vessel formation.

“SPARC is a protein most abundant during tissue remodeling and repair,” said Dr. Motamed. The protein has many functions including regulating the activity of growth factors. His studies are helping delineate the exact molecular mechanism through which SPARC inhibits basic fibroblast growth factor and vascular endothelial growth factor, both important to angiogenesis. Most tumor cells also express high levels of these growth factors. “In addition to making a host of factors themselves, cancer cells can also manipulate the cells of the host to facilitate their own proliferation and migration,” Dr. Motamed said.

SPARC – secreted protein acidic and rich in cysteine – is commonly expressed in the healthy remodeling of tissue, such as during embryonic development and wound- healing. It also is expressed in varying degrees by different cancers; expression is increased in breast cancer, prostate cancer and melanoma and decreased in ovarian cancer. “The bottom line is that the environment that supports the growth of cancer cells and their development into tumors is regulated by a multitude of factors. One of these factors is SPARC or a class of proteins like it,” Dr. Motamed said. Although the exact role(s) of SPARC in this complex process remains unclear – and may vary depending on the tissue in which it’s expressed – Dr. Motamed believes it’s an important role that takes him back to the cell matrix.

He’s looking at the SPARC expressed by prostate, breast and ovarian cancers to distinguish the role of SPARC expressed by these cancers and their supporting cells. Dr. Motamed, in collaboration with investigators at The Hope Heart Institute and the University of Texas Southwestern, will use the SPARC-less mouse model and a normal, control counterpart for these studies at MCG. He’ll also be looking at how the different tumors fare in the varying SPARC environments.

One of his many goals is to find the contribution of SPARC endogenous to the mouse, including exploring its potential for inhibiting and promoting tumors. It could be that SPARC’s more common role in inhibiting blood vessel formation is changed when tumors express yet another protein that cuts or cleaves SPARC, turning it into a promoter. It also could be that still other proteins cleave the cell matrix, releasing its previously dormant store of growth factors and, consequently, a huge burst of factors that can induce new blood vessel formation, he said.

“The school of thought is that there is a constant dialogue between the cancer cells and their so-called stromal cells, which are the supporting, non-cancerous cells within a tumor environment,” Dr. Motamed said. “It’s very obvious that you have to find out the players that regulate tumor cells or, the opposite, inhibit the growth of tumor cells, in this milieu that contains the cancer cells and supporting cells. The more you find out about all of these regulatory elements, the better off you are in battling tumors and cancer.”

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Support for Dr. Motamed’s research includes a four-year Howard Temin Award from the National Cancer Institute.

The Medical College of Georgia is the state’s health sciences university and includes the Schools of Allied Health Sciences, Dentistry, Graduate Studies, Medicine and Nursing, MCG Hospital and Clinics and the Children’s Medical Center.