Researchers Discover That Cancer Stem Cell Populations in Colorectal Cancers Are Diverse, Not Uniform

Discovery may lead to more precise treatments for advanced colorectal cancer

Researchers at ChristianaCare’s Cawley Center for Translational Cancer Research at the Helen F. Graham Cancer Center & Research Institute have demonstrated for the first time that microRNA (miRNA) expression leads to a diversity of cancer stem cells within a colorectal cancer tumor. This diversity of cancer cells may explain why advanced colorectal cancer is difficult to treat. Study results have been in the Journal of Stem Cell Research and Therapy.

The findings broaden the understanding of how miRNA expression adds to cancer stem cell diversity and may lead to more precise anti-cancer treatments for patients with advanced colorectal cancer. The research builds on prior discoveries by scientists at the Graham Cancer Center about how cancer stem cell activity contributes to the development and spread of colorectal cancer.

“Our research shows — at least in the laboratory — that there are different subpopulations of cancer stem cells in a tumor, and they may be driving the growth of the cancer,” said Principal Investigator Bruce Boman, M.D., Ph.D., MSPH, FACP, medical director of Cancer Genetics and Stem Cell Biology at the Graham Cancer Center. “In one subpopulation of cancer stem cells, its miRNA will shut down the stem cell genes that are expressed in another subpopulation, and vice versa, within the same tumor.”

^{From left: ChristianaCare researchers Lynn Opdenaker, Ph.D., Brian Osmond, Bruce Boman, M.D., Ph.D., Chi Zhang, Victoria Hunsu, Caroline Facey, Ph.D. Not pictured Victoria Stark, MS.}

The study focused on the composition of cancer stem cells within a colorectal cancer cell line (HT29) in the laboratory setting. Researchers evaluated the different cancer stem cell subpopulations that were identified by examining patterns of miRNA expression in each subpopulation and looking for differences. The researchers found that each of the four diverse subpopulations that were studied (ALDH, LRIG1, CD166 and LGR5) had a different miRNA expression or gene signature.

The researchers found that miRNA expression could inhibit the expression of messenger RNA (mRNA), which carries instructions from the DNA to encode specific proteins within cells. Therefore, miRNA, by controlling gene expression, dictate which proteins are contained in the stem cells. The researchers discovered the miRNA that are upregulated in certain cancer stem cell subpopulations are downregulated in other cancer stem cell subpopulations. In this way, differential miRNA expression leads to cancer stem cell heterogeneity within colorectal tumor tissue.

“It’s an early research finding and needs to be followed up with other experiments, but it has clear relevance to the clinic,” Boman said. “The question is: Can you target the miRNA to make cancer more sensitive to certain treatments? Because we know what the current anti-cancer treatments are targeting, we may be able to modulate or manipulate the cancer, so it becomes more sensitive to the treatment.”

^{Identification of a network of genes regulated by microRNAs in a cancer stem cell subpopulation.}

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For more than a decade, ChristianaCare’s researchers have contributed to the understanding of the role that cancer stem cells and miRNA expression play in the development and spread of colorectal cancer. This latest finding builds on earlier discoveries that examined a link between two cellular signaling pathways: retinoic acid (RA) signaling and wingless-related integration site (WNT) signaling, which are dysregulated by different gene mutations in colorectal tumors.

The RA signaling pathway induces growth arrest and differentiation of cancer stem cells. Notably, retinoic acid is effective against other types of cancer such as leukemia. The role of the WNT signaling pathway has an opposite effect on tumor growth. The WNT signaling pathway is activated by a mutation in the APC (adenomatous polyposis coli) gene in about 90% of cases of colorectal cancer. In APC mutant tissue, dysregulated miRNA expression may underlie an imbalance between the RA and WNT signaling, which then leads to intratumoral cancer stem cell heterogeneity. Still, this mechanism that may enable the cancer to proliferate could also provide clues on how to more effectively treat cancer.

“If you’ve got an imbalance between these two signaling pathways, then you’ve likely got a growth driver,” Boman said. “The question is: Can you suppress the WNT signaling and enhance the retinoic acid signaling?”

It may be possible to increase the sensitivity of colorectal cancer to retinoic acid-type drugs, and therapeutically shift the balance between different cancer stem cell subpopulations, thereby suppressing cancer growth. More research is needed to determine how targeted cancer therapies containing retinoic acid-type drugs may be made more effective against advanced cancer.

This research will be presented at the annual meeting of the American Association for Cancer Research in Orlando, Florida, April 14-19.

This research project was supported by a grant from the Lisa Dean Moseley Foundation.