Researchers at the University of Texas Medical Branch (UTMB) at Galveston have identified a biochemical pathway critical to the spread of tumors to new locations in the body. If this "survival pathway" can be successfully blocked under clinical conditions, the result could be a new therapy for colorectal cancer, according to research published online Dec. 15 in the Proceedings of the National Academy of Sciences.
Researchers focused on an enzyme known as Akt2, which is often also found at high levels in association with prostate, ovarian, breast and pancreatic cancers, according to the study.
Drawing on data from human colorectal cancer tissue samples, athymic "nude" mouse experiments and cell-culture studies and probing enzyme interactions with small interfering RNA, the scientists determined that Akt2 was critical to the survival of colorectal cancer cells in the late stages of the dangerous process of metastasis. At the same time, they also mapped the enzyme's interactions with other important proteins involved in colorectal cancer metastasis, laying the groundwork for the development of new therapies to stop the cancer's spread.
Piotr G. Ryachahou, MD, lead author of the paper and an instructor in the UTMB department of surgery, and colleagues suspected from previous work that Akt2 was significant in colorectal cancer metastasis. To profile the enzyme's involvement in metastasis, they examined tumor samples from patients with metastatic colorectal cancer and confirming that high levels of the enzyme were present.
Next, they conducted a series of experiments with mice bred to lack an immune response, injecting them with different colorectal cancer cell lines and using custom-designed siRNA treatments to decrease and increase the activity of Akt2, its relative Akt1 and the tumor-suppressing protein PTEN.
"When we decreased the Akt2 expression, we found there was really a significant difference," Ryachahou said. "Akt2 is essential for the later stages of colon tumor metastasis, but we also found that increased Akt2 alone is not enough for the growth of secondary tumors. For that, you need continuous PI3-kinase pathway stimulation and activation which can occur with absence of PTEN in these tumors."
Discoveries such as these, according to Evers, are "crucial to providing more directed therapies for the treatment of colorectal cancer metastasis based upon inhibition of specific components of the PI3-kinase pathway, thus allowing for a more personalized treatment regimen with potentially fewer side effects.”