Penn vet team points to new colon cancer culprit

IMAGE:Msi2 (stained red) is broadly expressed in intestinal tumors that result from loss of APC. Penn researchers believe activation of Msi2 downstream of APC loss drives metabolic activation of stem... view more

Colon cancer is a heavily studied disease -- and for good reason. It is one of the leading causes of cancer-related deaths worldwide, and its numbers are on the rise, from 500,000 deaths in 1990 to 700,000 in 2010.

This growth comes despite scientists' ever-increasing knowledge of the genetic mutations that initiate and drive this disease. Now, a team of researchers from the University of Pennsylvania has found evidence of a new culprit in the disease, a protein called MSI2.

Their findings provide a new target for potential therapeutic intervention in colorectal cancer and enhance our understanding of the complexities of cancer initiation and progression. Further studies of MSI2 may even help explain how the disease can return after lying dormant for years.

Christopher Lengner, an assistant professor in the Department of Animal Biology in Penn's School of Veterinary Medicine, was the senior author on the work. Collaborators from Penn Vet included co-lead authors Shan Wang and Ning Li as well as Maryam Yousefi, Angela Nakauka-Ddamba and Kimberly Parada. Additional co-authors from Penn included Fan Li, Brian Gregory and Shilpa Rao.

The Penn researchers teamed with Gerard Minuesa and Michael G. Kharas from Memorial Sloan-Kettering Cancer Center, Zhengquan Yu from China Agricultural University and Yarden Katz from the Broad Institute.

The research will appear in Nature Communications.

Lengner's research has long focused on how stem cells are able to differentiate into a variety of cell types, an ability known as stem cell potency. His lab's work dovetails with cancer research in that it is believed that a population of so-called cancer stem cells is responsible for sustaining cancer in the body once it is established, just as normal stem cells are responsible for continually renewing and sustaining our healthy cells.

In earlier studies, Lengner and Kharas had found that an RNA binding protein called MSI2 played a role in supporting the potency of hematopoietic stem cells. This same protein was also found to be highly active in blood cancers. Yet unlike other well-established genes that, when mutated, result in increased tumor formation, the MSI2 gene itself is not directly mutated in tumors. Rather, the normal, intact gene becomes highly activated as cancer progresses.

When MSI2 is active, the protein promotes cancer not by changing the expression of genes but by altering the ability of RNA to make proteins. Thus, until now, the contribution of MSI2 went undetected by traditional research techniques that are largely aimed at identifying mutations in DNA sequence and alterations in gene expression patterns.

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Penn vet team points to new colon cancer culprit