Heparan sulfate small molecules for contro tumor cell growth
Initial Award Abstract
Smoking-related cancers begin when the genetic material in a cell becomes mutated, causing the cell to multiply rapidly. In order to continue growing, cancer cells need nutrients from the surrounding environment. Many tumors receive those nutrients by stimulating the growth of new blood vessels, a process called angiogenesis. While angiogenesis occurs in healthy bodies, cancer cells lose regulation of this event during metastasis and become permanently activated.
Heparan sulfate (HS) glycosaminoglycans are a class of sulfated carbohydrates that play critical roles in mediating this progression in cancer cells. These carbohydrates decorate the surfaces of all cells and are potent regulators of cell growth. Studies suggest that the chemical structure of HS and its interactions with growth factors are altered in many human cancers. For instance, different HS molecules and growth factors are found on certain lung cancer types but not on healthy lung tissue. In addition, different concentrations of HS molecules are found in lung cancer cells, which can affect drug resistance and modify the sensitivity of normal and tumor cells to anti-cancer drugs. HS molecules also activate growth factors that promote angiogenesis and cancer metastasis.
Despite the well-established link between HS and lung cancer, a molecular-level understanding of how HS contributes to the development and/or progression of the disease has been challenging. Critical questions remain unanswered, including: How does HS activate specific growth factors? Which structures of HS are biologically important, and how do they impact the growth and metastasis of tumors? Our studies will address these questions by using a novel interdisciplinary approach that combines the tools of organic chemistry with biochemistry and cell biology.
Efforts to understand the roles of HS in cancer biology have been hampered by an inability to obtain discrete HS molecules for biological investigations. We will chemically synthesize HS compounds with defined structures and use them to unravel the mystery of how HS interacts with growth factors. Specifically, we will synthesize defined HS molecules and test their ability to alter cell growth via formation of fibroblast growth factor-receptor complexes. Once we are able to control formation of these complexes, we will systematically vary the chemical structure of the HS molecules to determine how HS structure influences cell growth. Lastly, we will examine the ability of our synthetic compounds to control important properties of lung cancer cells, including cell adhesion, migration, invasion, and transformation. These studies should lead to new insights into how this important class of molecules mediates cell growth in healthy versus cancer cells and may lead to novel molecular strategies for controlling the growth rate and metastatic properties of tumor cells. |