Writing in Nature Genetics, the team behind the study note that the PTEN gene is widely accepted to play a major role in prostate cancer.
The gene’s function is protective as it suppresses the growth of tumours in cancer. Although complete loss of the gene has been linked with metastasis, current evidence suggests it is not sufficient to trigger tumour progression.
However, the absence of PTEN, in combination with the deletion of the PML (another tumour suppressor) gene, is linked to a higher incidence of metastatic tumours, discovered scientists from the Beth Israel Deaconess Medical Centre (BIDMC), Harvard Medical School.
A possible causative effect was identified when the researchers “switched off” the PML gene in mice with slow-growing non-metastatic prostate cancer who were lacking the PTEN gene. This was sufficient to trigger metastasis in these animals.
They also found that a Western HFD was a stimulus that drove metastasis in PTEN-null mice.
Combined loss of PML and PTEN genes was also found to be a predictor of overall prostate cancer survival. Additionally, the researchers discovered that metastatic tumours lacking both suppressor genes produced abnormally large amounts of fats.
"It was as though we'd found the tumours' lipogenic, or fat production, switch," said senior author Dr. Pier Paolo Pandolfi , Director of the Cancer Centre and Cancer Research Institute at BIDMC. "The implication is, if there's a switch, maybe there's a drug with which we can block this switch and maybe we can prevent metastasis or even cure metastatic prostate cancer," he added.
"The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients," said Pandolfi. "Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer."
The scientists subsequently treated the mice with the obesity drug fatostatin and found that tumours shrank and did not metastasize.
Significance
Despite previous theories proposing the involvement of an HFD in cancer progression, this study provides a significant advance in the understanding of possible underlying mechanisms.
"Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking," said first author Dr.Ming Chen.
The results may assist the development of further mouse models for metastatic prostate cancer with greater predictive capability, suggest the researchers. The findings may also facilitate possible screening programmes to identify early-stage patients who lack both PTEN and PML genes.
In future, patients at high risk of developing metastatic cancer could be placed on low-fat diets, and/or treated with fat-blocking drug to prevent disease progression, the researchers suggested.
Indeed, the study findings might also incentivise people with prostate cancer to improve their diet. "The data are tremendously actionable, and they surely will convince you to change your lifestyle," Pandolfi said
“Our results provide a potential roadmap for targeted therapies tailored to individual patients for the prevention and treatment of metastatic cancer,” he concluded.
Source: Nature Genetics
Published online, doi: 10.1038/s41588-017-0027-2
“An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer”
Authors: Ming Chen, Pier Paolo Pandolfi et al