Tumor Suppressor Gene May Actually Promote Colorectal Cancer Metastasis

It may now be possible to combat metastatic colorectal cancer in a whole new way. Researchers at the University of Missouri are now reporting that a gene thought to suppress cancer may actually promote metastatic disease in some patients with colorectal cancer.

Considering cancer deaths are mainly due to tumor recurrence and metastasis to other organs, researchers report that these findings may have clinical relevance with regard to how colorectal cancer is treated.

“The gene known as Sprouty2 has previously been shown to protect against metastasis or the spreading of cancer to other parts of the body in breast, prostate and liver cancer,” said  lead study author Sharad Khare, PhD, who is an associate professor of research in the Division of Gastroenterology and Hepatology at the University of Missouri, in a news release . “However, our recent molecular studies found that this gene may actually help promote metastasis instead of suppress it.”

For more than 3 years, Khare studied Sprouty2 in cancer cell models, mouse models, and human biopsy samples. Sprouty (SPRY) is an intracellular regulator of receptor tyrosine kinase signaling involved in growth, differentiation, and tumorigenesis.

According to a recent publication in Oncogene, Khare and colleagues found that the gene functions differently in colorectal cancer than in other types of cancers. Sprouty2 is known to block molecular circuits to prevent cancer cells from growing and spreading to other parts of the body. However, the researchers found that Sprouty2 may increase the metastatic ability of cancer cells instead of suppress it in colorectal cancer. Khare believes this occurs when the gene is upregulated or supercharged. 

Four family members of SPRY (SPRY1–4) were identified in the current study, and the researchers investigated the mechanisms by which SPRY regulates epithelial– mesenchymal transition (EMT) in colorectal cancer. The researchers found that SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human colorectal cancer. The study also suggested that the suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors. They report that this suppression of SPRY2 significantly increased E-cadherin expression and may drive EMT and serve as a biomarker of poor prognosis in some patients with colorectal cancer.

“This finding is a very significant step in our understanding of metastasis in colorectal cancer, but it’s important to note that we believe this phenomenon may occur in only a subset of colorectal cancer patients,” said Khare. “We don’t yet know why this is the case, but we hope to determine if there is a correlation between the up-regulation of this gene and the life expectancy of patients with colorectal cancer. Future studies will help us understand who may be at risk, and ultimately, if personalized treatments can be planned to target this gene.”