Scientists discover role of two specific HOX genes in colon cancer development

In breakthrough colon cancer research, scientists at Christiana Care Health System's Center for Translational Cancer Research (CTCR) of the Helen F. Graham Cancer Center & Research Institute have discovered that over-expression of HOXA4 and HOXA9 genes in colon cancer stem cells promotes cell replication and contributes to the overpopulation of stem cells that drives colon cancer development.

The findings suggest treatment with vitamin A derivatives, called retinoid drugs, could provide a therapeutic strategy for decreasing the expression of these HOX genes and for targeting highly resistant cancer stem cells.

The study, led by Bruce Boman, M.D., Ph.D., MSPH, FACP, medical director of Cancer Genetics and Stem Cell Biology at the CTCR, is the cover story in the February 2018 issue of the Journal of Cellular Physiology, Vol. 233, Issue 2.

"A few other labs have looked at the role of HOX genes in colon cancer," Dr. Boman said, "but we are the first to identify the role of two specific HOX genes in colon cancer stem cell overpopulation, which drives tumor growth."

Dr. Boman's prior research contributed to the understanding of normal stem cells and how cancer stem cells play a role in the development and spread of colorectal cancer. Previously, his lab helped identify that these long-lived, uncommon cells start out as tissue stem cells that become cancer stem cells when certain mutations or mistakes occur in the genes that regulate cell renewal and overpopulation.

More recently, Dr. Boman and his team of scientists at the Graham Cancer Center focused on the role of HOX genes because these genes are known to be master regulators of stem cells, and because HOX gene expression has been found to malfunction in various types of cancer. Gene expression works as an on/off switch that regulates how cellular components are made. Adjusting the level of gene expression can directly impact cancer cell development and the drive to self-replicate.

What the team discovered was that lowering HOXA4 or HOXA9 expression in colon cancer stem cells decreases their self-renewal ability, reducing cell population, and inhibiting cell proliferation. The investigators concluded that therapeutically targeting HOX gene expression could reduce the self-renewal ability of malignant stem cells during cancer development.

To test this hypothesis, they chose All-Trans Retinoic Acid (ATRA), one of the most commonly investigated and clinically tested retinoic acid derivatives. Previous studies have shown that ATRA can reduce self-renewal ability in a number of other cancers.

Dr. Boman and his research team found that ATRA down-regulates HOX gene expression, decreases gene expression of a known stem cell biomarker (ALDH1) and reduced stem cell viability and renewal. "Our findings point to a number of possibilities for developing more effective, stem cell targeting therapies for advanced colorectal cancer," Dr. Boman said.

Colon cancer is a leading cause of cancer-related deaths in the United States. Conventional research over the last 50 years has shown that tumors undergo a series of genetic mutations that lead to the unchecked growth of tumors and their progression to metastatic cancer. Traditional therapies designed to kill the bulk of cancer tumor cells continue to fall short of a cure for advanced, drug-resistant colon cancers.

"The discovery of cancer stem cells has been nothing less than a paradigm shift," Dr. Boman said. "Our thinking has shifted to the insight that cancers originate in tissue stem cells through dysregulation or malfunction of the self-renewal process and that cancer stem cells drive tumor growth."

"Our work and that of others has shown that the optimal way to treat cancer, especially advanced cancer, is to eliminate cancer stem cells," he said. "Given that cancer stem cell targeted agents are now entering clinical trials, we will soon know if this is the case."

"Dr. Boman's breakthrough research directs our focus to the roots of cancer's origins at the molecular and cellular level," said Nicholas J. Petrelli, M.D., Bank of America endowed medical director of Christiana Care's Helen F. Graham Cancer Center & Research Institute. "His work highlights the mission of the Center for Translational Cancer Research, shortening the path from bench to bedside for targeted therapies that can improve survival and quality of life for patients with drug resistant, advanced colorectal cancer."

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