Gene Loss Provides Important Clue About Prostate Cancer Bone Mets

There are over 20 known lines of prostate cancer (PCa) and some are more able to metastasize (spread) beyond the gland. The majority of PCa cell lines rarely pose a threat to life, especially when diagnosed early. However, the aggressive minority is dangerous. Thanks to today’s ability to map an entire DNA sequence within a single cell (the cell’s genome), it is increasingly possible to identify specific “biomarkers” that may tell us if a PCa patient has a more dangerous type of cancer, and needs to be treated aggressively.

Prostate cancer that spreads to the bones

When PCa tumor cells break away from the primary tumor in the prostate, they circulate in the blood (circulating tumor cells, or CTCs) until they are able to anchor themselves in another location. CTCs from prostate cancer are particularly drawn to bone because it is rich in blood, cell nutrients, and growth factors that bones use to constantly replace old bone cells with new ones. If CTCs are successful in forming their own colony in the pelvis, spine, or other skeletal location, it is called bone metastasis, or simply bone mets. Once in place, they start hijacking the bone’s resources to nourish themselves and build their own blood supply.

A missing gene makes bone mets more likely

Much is known about the genomics of cells from localized PCa because prostate biopsies and specimens from radical prostatectomy yield an abundance of cells to study. However, very little is understood about the characteristics of cells from PCa bone mets. Metastasis is an inefficient process involving many obstacles and challenges¹. What is it about these cells that allows them to behave so aggressively and metastasize successfully? A research group from a number of British centers developed a theory based on genomic analysis of PCa bone mets cells themselves².

It is already known that many genes and molecular messengers in healthy cells are tasked with making sure the cells don’t go out of control and start forming a tumor. A large number of such genes and molecules are already known, but mysteries remain. In this case, the research team discovered an interesting and unusual pattern in the genome of the PCa bone mets cells. A particular gene called FBXL4 was commonly missing from a specific location on the genome. When the scientists went looking for the same phenomenon in specimens from early stage PCa cases, they found FBXL4 deleted in only 13.8%—and almost no deletions in three cell lines known to be indolent. However, CTCs had a higher rate of missing FBXL4 than early stage PCa cells, suggesting that breakaway tumor cells with FBXL4 deleted have the capacity to colonize bone.

The team also found the loss of FBXL4 was strongly linked with higher PSA, higher Gleason grade, higher clinical stage of tumor, and greater extent of localized disease. It is not surprising, then, that loss of FBXL4 is also associated with death from PCa.

Does this mean that the FBXL4 gene plays a role in terms of helping inhibit or prevent the spread of prostate cancer? The authors wrote, “The relatively low frequency of FBXL4 genomic region loss in primary tumours and its significant increase in frequency in metastatic samples … supports the hypothesis that FBXL4 is a gene that suppresses prostate cancer metastatic progression.”

Not the whole story

The publication of this research is an important contribution to understanding prostate cancer bone mets and how they succeed against long odds. But it doesn’t claim to be the sole explanation – indeed, much more research is needed – nor does it tell us how FBXL4 gets deleted from a normal prostate cell genome.

On the other hand, it offers hope because the information it provides may one day contribute to a new approach to treatment, or even prevention. That would be a great day for prostate cancer patients.

Learn more about the symptoms of prostate cancer bone mets.

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¹ Massagué J, Obenauf AC. Metastatic colonization by circulating tumor cells. Nature 529, 298–306 (21 January 2016)
² Stankiewicz E, Mao X, Mangham DC, Xu L et al. Identification of FBXL4 as a metastasis associated gene in prostate cancer. Sci Rep. 2017 Jul 11;7(1):5124.