Researchers map new path to colon cancer therapy

December 15, 2008

GALVESTON, Texas -- University of Texas Medical Branch at Galveston researchers have identified a promising new target in the battle against colorectal cancer -- 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 would be a much-needed new therapy for colorectal cancer, the second leading cause of cancer death in the United States.

The researchers' findings, published online the week of December 15 in the Proceedings of the National Academy of Sciences, focus on an enzyme known as Akt2, which is often also found at high levels in association with prostate, ovarian, breast and pancreatic cancers.

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-- the development of secondary tumors at a distance from a primary tumor. 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.

"Metastasis is a really complicated process," said Dr. Piotr G. Rychahou, lead author of the paper and an instructor in the UTMB department of surgery. "Through a complex cascade of events, cancer cells escape from the original tumor and invade surrounding tissues until they reach a blood or lymphatic vessel. Next, they cross the wall of the vessel and enter the circulation in order to reach a target organ--again crossing through the vessel wall --and grow into secondary tumors that we actually detect in patients. To survive this hazardous solo journey, invade a foreign organ and proliferate there, cancer cells need support from intracellular survival pathways. Akt2 is part of the PI3-kinase / Akt pathway, one of the strongest pro-survival signaling pathways."

Rychahou and his colleagues, including senior author and director of the UTMB Sealy Center for Cancer Cell Biology Dr. B. Mark Evers, suspected from previous work that Akt2 was significant in colorectal cancer metastasis. To profile the enzyme's involvement in metastasis, they started at the end of the metastatic road: examining 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 athymic "nude" mice (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," Rychahou 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"
-end-
Other authors of the PNAS paper "Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis" include research assistant Junghee Kang, graduate students Pat Gulhati, Hung Doan and Andy Chen, Dr. Shu-Yuan Xiao and Dr. Dai Chung from the department of surgery, department of pathology and the Sealy Center for Cancer Cell Biology at UTMB.

University of Texas Medical Branch at Galveston

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.