gastroenterology

Lab Notes – Summer 2017

Melanoma’s Signature

illustration of a melanoma cell

Dangerous melanomas likely to metastasize have a distinctive molecular signature, UConn Health researchers reported in the February issue of Laboratory Investigation. Melanomas are traditionally rated on their thickness; very thin cancers can be surgically excised and require no further treatment, while thick ones are deemed invasive and require additional therapies. But melanomas of intermediate thickness are harder to judge. The researchers measured micro-RNAs produced by melanoma cells and compared them with the micro-RNAs in healthy skin. Micro-RNAs regulate protein expression in cells. The team found that melanomas with the worst outcomes produced lots of micro-RNA21 compared to melanomas of similar thickness with better outcomes. In the future this molecular signature could help dermatologists decide how aggressively to treat borderline melanomas.


Chili Pepper and Marijuana Calm the Gut

The medical benefits of marijuana are much debated, but what about those of chili peppers? It turns out that when eaten, both interact with the same receptor in our stomachs, according to UConn Health research published in the April 24 issue of Proceedings of the National Academy of Sciences. The scientists found feeding mice chili peppers meant less gut inflammation and cured those with Type 1 diabetes. Why? The chemical capsaicin in the peppers bonds to a receptor found in cells throughout the gastrointestinal tract, causing the cells to make anandamide — a compound chemically akin to the cannabinoids in marijuana. The research could lead to new therapies for diabetes and colitis and opens up intriguing questions about the relationship between the immune system, the gut, and the brain.

illustration of chili peppers and marijuana in the gut


Isolating Their Target

brain scan

Brain cells of individuals with Angelman syndrome fail to mature, disrupting the ability of the cells to form proper synaptic connections and causing a cascade of other developmental deficits that result in the rare neurogenetic disorder, according to UConn Health research. Neuroscientist Eric Levine’s team used stem cells derived from Angelman patients to identify the disorder’s underlying neuronal defects, an important step in the ongoing search for potential treatments and a possible cure. Previously, scientists had relied primarily on mouse models that mimic the disorder. The findings were published in the April 24 issue of Nature Communications. While Levine’s team investigates the physiology behind the disorder, UConn developmental geneticist Stormy Chamberlain’s team researches the genetic mechanisms that cause Angelman.


The Cornea’s Blindness Defense

eye

The formation of tumors in the eye can cause blindness. But for some reason our corneas have a natural ability to prevent that from happening. Led by Royce Mohan, UConn Health neuroscientists believe they have found the reason, findings that will be detailed in September’s Journal of Neuroscience Research. They link the tumor resistance to a pair of catalytic enzymes called extracellular signal-regulated kinases 1 and 2. When ERK1/2 are overactivated in a specific type of cell, the “anti-cancer privilege of the cornea’s supportive tissue can be overcome,” says Mohan. That happens in the rare disease neurofibromatosis-1. “These findings may inform research toward developing better strategies for the prevention of corneal neurofibromas,” says Dr. George McKie, cornea program director at the National Eye Institute, which funded the study.

Predicting Colon Cancer:

UConn Health Researchers Redefine ‘Early Detection’

By Chris DeFrancesco

Illustration of colon with areas highlighted and given warning signs


Find cancer early enough and you can treat it. Predict it before it develops and you can prevent it altogether.

Thanks to volumes of epidemiological data they have amassed, UConn Health researchers believe they are closing in on ways to identify who’s most at risk for colorectal cancer by analyzing cells from lesions that, if they are to become cancerous, are years away from doing so.

Once this can be figured out, doctors and patients would have a larger window of time to take steps to stop the cancer before it starts.

In the laboratory of Daniel W. Rosenberg in UConn Health’s Center for Molecular Medicine, concurrent studies — epidemiological, genomic, and molecular — are ongoing and are expected to yield a series of published papers this year and next. One, which describes how the Rosenberg lab uncovered evidence of the origins of colorectal cancer that historically have been poorly understood, was published in the June edition of Molecular Cancer Research, a major scientific journal of the American Association for Cancer Research.

We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.

Cancer evolves from what is known as neoplasia — or new, abnormal growth of tissue. Not all neoplasias become malignant tumors, but they are considered an early warning sign of possible cancer.

“Understanding early neoplasia has become such a major focus at the National Cancer Institute — how do we characterize these early changes so we can prevent cancer,” says Rosenberg, HealthNet Inc. Endowed Chair in Cancer Biology and professor of medicine, “and I believe we’re at the forefront of answering this question.”

MD/Ph.D. candidate Allen Mo, first author on the Molecular Cancer Research paper, says colon cancer is thought to be an epithelial disease, meaning that it starts with a mutation in the tissue that lines the surface of the colon (the epithelium), and grows and then invades the underlying support tissue.

“People historically believed these are separate compartments, that there is no interaction between the epithelium and the support tissue until the cells become cancerous and break through the membrane,” Mo says. “We’ve been able to demonstrate that, even at the very early stage, prior to the polyp stage, the supportive tissue is actually influencing how these epithelial initiate cells are evolving.”

That’s important because it provides another potential early intervention point — if scientists can figure out a reliable way to make alterations to the signaling pathways between the two tissue types, perhaps they could influence how the mutated cells progress.

The Devers Data

The work includes collaborators from both within and outside the institution, but central to all of it is Dr. Thomas Devers, a UConn Health gastroenterologist whose volume of consecutive colonoscopies over the past five-and-a-half years has yielded data from 5,000 patients. The resulting demographic database has been powering the engine driving the research that has helped substantiate epidemiological findings, such as how smoking completely cancels the protective properties of aspirin, how consumption of diets rich in Omega-3 fatty acids appear to reduce risk of early neoplasia in the colon, and how walnuts may have protective properties, as described in a study recently published in Cancer Prevention Research.

“Dr. Devers routinely screens patients at a resolution that only a handful of clinicians are doing,” Rosenberg says.

Devers uses a high-definition endoscope with contrast dye-spray that enables him to detect tiny — less than 5 mm — lesions that are scattered throughout the colon.

“Many of the subjects have already returned for follow-up [surveillance] colonoscopy, so we actually have genomic data from three and five years ago that we can use to predict the possibility they may develop advanced adenomas or even cancer,” Rosenberg says. “We’re actually at the point now where we can follow the impact of these early changes over time.”

The work involves the intensive application of bioinformatics, the collection and analysis of complex biochemical and biological information.

What the Earliest Changes Can Reveal

Among the tiny lesions of particular interest are those known as aberrant crypt foci (ACF), which represent the earliest detectable precancerous change in the human colon. ACF tend to be detected less frequently during conventional colonoscopy, occur throughout the colon, and are the source of tissue that the Rosenberg lab uses for many of its analyses.

“We’re one of the only places in the country that actually look for these very early lesions,” says Mo, whose work has been instrumental to a number of ongoing studies in the Rosenberg lab.

“Most people study colon cancer development in the context of polyps as the earliest lesion,” Rosenberg says. “But we’re going one step earlier, with our focus on ACF. ACF present a unique opportunity to study the risk factors that may predispose the development of colon neoplasia, and may help to guide us toward potential interventions that may actually eliminate neoplasia prior to the appearance of polyps.”

Devers says the ACF he’s been finding in one particular area of the colon can be very telling when it comes to predicting future cancer risk.

“Part of our hypothesis is, we’re going to find these tiny lesions on the right side of the colon that have a lot meaning, that are only present in a small percentage of the population compared to the people who have tiny lesions in the rectosigmoid (the lower part of the colon), which everybody has,” Devers says. “And by finding these tiny lesions in the right side of the colon, you may want to screen those people more frequently.”

Biopsies and data from about 300 patient research volunteers have been the basis of several studies, including a collaboration with scientists at the Van Andel Institute in Grand Rapids, Mich., and The City of Hope in Duarte, Calif.

“We’ve done a complete genome-wide analysis of the epigenetic changes present within these tiny lesions, something that has never been done before,” Rosenberg says. “We’re uncovering all these interesting changes that occur to a person’s epigenetic profile years before they may develop a more advanced neoplasia. Much of this transformative epigenetic work was been performed by Matthew Hanley, a fifth-year graduate fellow in my lab. The question is, why we are interested in this ‘predictive’ profile? We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.”

Often Hidden, Likely Telling

Another finding: some people seem to have a higher likelihood of forming what are known as sessile serrated adenomas (SSA) in the upper part of their colon. SSA, which also tend to be harder to detect, carry a strong likelihood of progressing, and may contribute to 20 to 30 percent of colorectal cancers.

“We believe that missed right colon cancers, or interval colon cancers, are related to these serrated adenomas,” Devers says.

SSA are larger than ACF but are also very difficult to catch during colonoscopy because of their flat shape and their tendency to be camouflaged in mucus along the colon wall. It takes a high-definition scope and experience — Devers has both — to find them.

“We’re able to actually identify thepeople who form this lesion, then go back to the epidemiological database and develop risk profiles as to which people are more likely to form that type of lesion,” Rosenberg says.

On the molecular level, Rosenberg’s lab routinely uses laser capture microdissection, which enables scientists to select and retrieve small groups of cells from a single biopsy. From there, they can apply genomic technologies to particular cells and screen for cancer-related mutations and genome-wide alterations. This technique was used in the research behind the Molecular Cancer Research paper.

“Early neoplasia has become a very hot area, and because of Dr. Devers, here we probably have accumulated the largest repository of human early neoplastic lesions anywhere in the world,” Rosenberg says. “With this amazing resource, we can now begin to define many of the key changes that are happening at this very early stage. It’s never been done before.”

The Doctors Are In – Winter 2015

UConn Health welcomes the following new physicians:


Ridhi Bansal, MD

Specialties: Internal Medicine, Primary Care
Location: Canton


Philip M. Blumenshine, MD, MAS., M.Sc.

Psychiatry Emergency Department Medical Director

Specialty: Psychiatry
Locations: Farmington


Ethan I. Bortniker, MD

Specialty: Colon Cancer Prevention, Gastroenterology
Location: Farmington


Tilahun Gemtessa, MD, M.Sc.

Specialty: Infectious Diseases
Location: Farmington


Matthew Imperioli, MD

Specialty: Neurology
Location: Farmington


Neha Jain, MD

Specialty: Psychiatry, Geriatric Psychiatry
Location: Farmington


David Karimeddini, MD

Specialty: Radiology
Location: Farmington


Hsung Lin, DMD

Specialty: Family Dentistry
Location: Storrs Center


Janice Oliveri, MD

Specialty: Internal Medicine
Location: Farmington


Houman Rezaizadeh, MD

Specialty: Gastroenterology
Location: Farmington


Bernardo Rodrigues, MD

Speciaty: Neurology
Location: Farmington


Lenora S. Williams, MD

Specialty: Obstetrics and Gynecology, Women’s Health
Location: Storrs Center


Visit UConn Health’s online physician directory for information about all our specialists.