Quite simply stated, if we can figure out how to prevent RhoC activation we can stop metastases from occurring. This is particularly relevant for certain cancers such as breast, prostate and melanoma, which are caught early and have the potential for metastasis. One other potential clinical use is that RhoC and other molecules involved in the RhoC-driven metastasis can be used as prognostic markers.
This is an interesting question that researchers have been trying to address for a couple of decades now. Essentially, the tumor cells need to be competent on a number of levels to become invasive and migratory. Basically, the cells need to be able to be able to separate from other cells, respond by changing shape, produce enzymes that degrade the matrix around it. There are many other attributes that a cell needs in order to be metastatic in the body.
We find that these signals come from the microenvironment. Many of the growth factors that activate RhoC are found in the circulation, particularly in cancer patients. The tumor cells themselves also produce many of these factors as well. Further, upon arrive at certain metastatic sites the prevalence of certain extracellular matrices can also activate RhoC.
Inflammatory breast cancer (IBC) is very different from other types of breast and should be thought of completely independently. Primary IBC tumors form as sheets or cords of tumor cells in the breast but they quickly invade into the dermal lymphatic vessels and form emboli. Because of these features IBC typically cannot be visualized by mammography.
Inflammatory breast cancer cells rapidly invade the dermal lymphatic vessels. The tumor cells form emboli within the dermal lymphatics and are thought to rapidly spread throughout the body. When diagnosing IBC, skin punch biopsies are taken and analyzed for emboli within the lymphatic vessels.
We have found several signaling processes that activate RhoC in cells depending on tumor type. In prostate cancer cells, we find that both growth factor activation (specifically insulin-like growth factor 1) and binding to certain extracellular matrices such as type I collagen activate RhoC. In pancreatic cancer, we find that RhoC activation via growth factors is negatively regulated by other types of signaling molecules, such as the scaffolding molecule caveolin-1. In inflammatory breast cancer, we find that growth factors such a epidermal growth factor (EGF) activates RhoC. In this case we have also found a relationship with caveolin-1 as well, except in this case it is the inverse of what we find in pancreatic cancer; caveolin-1 is a positive regulator of RhoC activation.
Our early work compared the role of RhoC GTPase with that of other highly similar GTPases, specifically RhoA and RhoB, in different cancer types and in expressing RhoC in normal mammary epithelial cells. We found that RhoC is required to drive migration and invasion of tumor cells. Further, expression of RhoC in normally mammary epithelial cells made those cells motile as well. Later experiments demonstrated that knockout or knockdown of RhoC led to prevention of invasion and metastasis of tumor cells.
RhoC GTPase is normally found in cells that are motile, such as immune cells that migrate to sites of infection. RhoC is typically not expressed in cells that cancers arise from (epithelium). In motile immune cells, RhoC drives reorganization of the actin cytoskeleton allowing those cells to move. Metastatic cancer cells gain RhoC expression and activation (abnormally), which drives the cells ability to invade and migrate similar to that of normal immune cells.
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