Researchers have identified the gene responsible for setting off a cellular chain reaction that causes prostate cancer to metastasize to the bone, making it almost impossible to treat. The discovery could have significant implications for treating prostate cancer and other solid tumor types in which the gene is present.
Bone metastases are common in all types of advanced cancer, but particularly among patients with prostate and breast cancers. When prostate cancer metastasizes to bone, it’s often a death sentence, as there are no effective therapies to treat the spread.
The biological processes underlying prostate cancer growth and metastasis involve complex interactions between tumor cells and the microenvironment. It’s known that a particular gene, melanoma differentiation-associated gene-9 (MDA-9), found not only in cancer cells but all forms of tissue, is a major contributor to the spread of cancer, but the ‘how’ wasn’t completely understood.
Now, a new study by researchers at the Virginia Commonwealth University (VCU) Massey Comprehensive Cancer Center and the VCU Institute of Molecular Medicine (VIMM) has examined the role of MDA-9 in the spread of prostate cancer and discovered, for the first time, how it sets off a cellular chain reaction that leads to metastasis and empowers tumor cells to take control in the bone itself.
“MDA-9 plays a role from A to Z in the tumor; it is essentially the gene that directly facilitates tumor progression and metastasis,” said Swadesh Das, a co-corresponding author of the study.
The pathway identified by the researchers has many steps. MDA-9 activates platelet-derived growth factor AA (PDGF-AA) in tumor cells, a protein that regulates cell growth and division, and releases it into the bone environment. There, PDGF-AA binds with receptors on bone marrow-mesenchymal stromal cells (BM-MSCs), which are multipotent stem cells important for making and repairing skeletal tissues. The stromal cells interact with MDA-9 to activate the Hippo signaling pathway, which is responsible for cell regeneration. This leads to the release of a smaller migration-stimulating protein, the chemokine CXCL5, which attracts cancer cells into the bone tissue; this causes the production of more CXCL5 and the luring in of more cancer cells cyclically. In addition to attracting cancer cells into the bone tissue, CXCL5 also enhances the reproduction of osteoclasts, a subset of bone cells that destroy bone.
“This study is a definitive demonstration of communication between prostate cancer cells and normal BM-MSCs within the tumor microenvironment, and how this biological conversation between them allows for metastatic cells to spread to and proliferate in bone,” Das said.
The researchers found that by knocking out MDA-9 in prostate cancer cells, this domino-like pathway could be interrupted, preventing the spread of the disease. They also found that removing MDA-9 from bone cells did not negatively affect the health of bone tissue.
While the researchers observed the MDA-9 pathway in animal, human, and patient-derived prostate cancer cells, they believe their findings have implications for other solid tumor types in which MDA-9 is present, including brain, breast, melanoma, lung and pancreatic cancers.
The researchers have developed a novel inhibitor drug in-house at VCU in collaboration with InVaMet Therapeutics that has shown promise in studies targeting MDA-9 in cancer.
“We’re close to something that may go into the clinic,” said Paul Fisher, another corresponding author. Future studies will investigate the use of MDA-9 inhibitors in clinical tumor samples and, ultimately, in patients.
The study was published in the journal PNAS.
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