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

Apr 4, 2023

4 min

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.

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.

You might also like...

Check out some other posts from ChristianaCare

3 min

First in Delaware to Offer MR-Guided Ultrasound for Treatment of Essential and Parkinson’s Tremor

Revolutionary technology gives patients immediate relief from debilitating tremors without the need for invasive surgery. ChristianaCare is the first health care provider in Delaware to offer FDA-approved focused ultrasound treatment for people suffering from essential tremor and Parkinson’s disease. The new option – called MR-guided focused ultrasound – uses sound wave energy to destroy precise areas of brain tissue that is the source of the tremor. No surgical incision or anesthesia is necessary, and many patients experience immediate and significant reduction in tremors, which can make daily activities challenging. Dr. Martello explains that the procedure involves the use of high-frequency sound waves directed with pinpoint precision by magnetic resonance imaging to ablate, or burn, the focal point deep within the brain that is causing tremors. “This minimally invasive technology dramatically improves the lives of patients with essential tremor and tremor-dominant Parkinson’s who haven’t fully responded to traditional treatments,’’ said Justin Martello, M.D., director of the Parkinson’s and Movement Disorders Programs, and Focused Ultrasound Program at ChristianaCare. What is tremor? Tremor is a neurological condition that includes involuntary shaking or trembling movements in one or more parts of the body. It most commonly affects the hands and can make daily tasks such as writing, eating and using a computer or phone extremely difficult. Tremor affects approximately 1% of the population overall and 5% of adults age 60+. It is expected to increasingly impact Delawareans as the state’s population ages. Essential tremor is the most common type of tremor. It can occur at any age but is most common in older adults. Tremor is also the most well-known symptom of Parkinson’s disease. An estimated 1.5 million Americans suffer from Parkinson’s disease, a progressive neurodegenerative disease that affects movement and can also affect speech, balance and cognitive function. A newer, better option for patients who don’t respond to medications The procedure of MR-guided focused ultrasound involves the use of high-frequency sound waves directed with pinpoint precision by magnetic resonance imaging to ablate, or burn, the focal point deep within the brain that is causing tremors. Patients are fitted with a frame affixed to a specialized helmet that combines the focused energy of more than 1,000 high-frequency sonic beams directed through the skull. The treatment does not require cutting through the skull, or radiation, as in gamma knife technology. “Today, there are basically three options for managing tremor,” said Pulak Ray, M.D., of Delaware Neurosurgical Group and associate director of the Focused Ultrasound program. “The first is medication, which is effective and affordable for many patients, but its effectiveness tends to diminish over time. The second is deep-brain stimulation, which is the most invasive and costly treatment option. The newest is MR-guided ultrasound, which tends to be the preferable option for most patients who do not respond well to medication, because it is a simple, non-invasive outpatient procedure that is highly effective, safe and produces instant results.” Benefits of MR-guided Focused Ultrasound MR-guided focused ultrasound reduces tremor immediately, with shorter recovery time, lower risk of side effects and lower associated health care expenses compared to surgical alternatives. This treatment dramatically improves patient experience and quality of life for people with Parkinson’s disease or essential tremor. For many patients, MR-guided ultrasound reduces their dependence on caregivers to assist with activities of daily living. Candidates must first undergo a CT scan to ensure a skull density sufficiently thick to accommodate the procedure. The patient is awake during the procedure and situated within an MRI machine for real-time imaging of the brain. The physician tests the precise location by heating the area, then ensuring the patient is able to control tremors by tracing lines on a spirograph. At that point, the physician then permanently ablates the focal point, usually a sphere a few millimeters in length. “Our team is very excited to bring this technology to Delaware and to open up access to potentially life-changing treatment that until now has required long wait times and significant travel for patients,” said Kim Gannon, M.D., Ph.D., medical director of the comprehensive stroke program and physician executive of Neuroscience Service Line at ChristianaCare. “Many tremor patients have suffered for years or even decades with this debilitating and progressive condition and helping them live a more active and independent lifestyle is extremely rewarding.” MR-guided focused ultrasound is covered by Medicare and most insurance plans.

2 min

Wilmington Campus Receives $1 Million Donation From the Rocco A. and Mary Abessinio Foundation

ChristianaCare has received a $1 million gift from The Rocco A. and Mary Abessinio Foundation Inc. in support of ChristianaCare’s Wilmington Campus. “All families and communities deserve the excellent care that Wilmington Hospital and ChristianaCare provide,” said Rocco and Mary Abessinio. “It is an honor for our family to support the health and wellbeing of the Wilmington community.” The funds will support areas of greatest need, including the expansion of patient care initiatives aimed at reducing disparities in screening and treatment for cancer and cardiovascular disease in the city of Wilmington. “We are tremendously grateful to the Rocco A. and Mary Abessinio Foundation for their continued, generous support of the Wilmington Campus – a vital resource serving the greater Wilmington community,” said Janice Nevin, M.D., MPH, ChristianaCare president and CEO. “With their help, we are closing gaps in health disparities and improving health for everyone, including some of Delaware’s most vulnerable populations.” The Rocco A. and Mary Abessinio Foundation provided a $1 million gift in 2014 for the redesign and renovation of the health center, which was then named the Rocco A. Abessinio Family Health Center at Wilmington Hospital. The health center is home to three primary care practices and other programs and services that offer high-quality health care, wellness and preventive health visits for people of all ages, regardless of their income or ability to pay. “As a result of the Abessinio family’s longstanding partnership and investment in our mission of service, we are making significant progress in addressing disparities and building strong and healthy communities,” said LeRoi S. Hicks, M.D., MPH, FACP, campus executive director of ChristianaCare’s Wilmington Hospital. A Wilmington landmark in the heart of the city, the ChristianaCare Wilmington Hospital has been serving the diverse medical needs of the city and surrounding region for over 125 years. “Philanthropy is essential to ChristianaCare’s mission of service to our community, and we extend our heartfelt thanks and appreciation to Rocco and Mary Abessinio for their inspiring and visionary philanthropic leadership in support of the Wilmington Campus,” said Dia Williams Adams, MPA, vice president of philanthropy at ChristianaCare. “Their gift is a legacy that not only allows us to increase our ability to make a positive impact on patients and community, but honors the incredible work that our caregivers do every day.” For more information about ways to support ChristianaCare’s mission of service to the community, visit:

5 min

This Is a Critical Moment: Delaware Must Not Go Backward in Health Equity

The proposed Delaware House Bill 350 is well-intended but would have terrible consequences for Delaware’s most vulnerable populations. There is a better way. By LeRoi S. Hicks, M.D., MPH, FACP As a Black physician who has dedicated his 25-year career to understanding and addressing health equity, I am deeply concerned about Delaware’s proposed House Bill 350, which aims to address rising health care costs by establishing a body of political appointees that would oversee the budgets of Delaware’s nonprofit hospitals. While the goal of bending the cost curve in health care may be well-intentioned, this bill will have horrific consequences for Delaware’s most vulnerable populations, including Black people, Hispanic people and other groups that have been traditionally underserved in health care. We can and must work together to solve this problem and provide the right care, in the right place, at the right time. A tale of two cities To borrow a phrase from Charles Dickens, Delaware, like much of America, is a tale of two cities. The experience of life—including a healthy, safe environment and access to good-quality health care—is vastly different depending on where you live and your demographic background. In the city of Wilmington, for example, ZIP codes that are just a few miles apart represent more than 20 years difference in life expectancy. This is not OK—it’s a sign that we have serious structural problems in our communities that are causing harm to people and making their lives shorter. Importantly, chopping $360 million out of Delaware’s hospital budgets, as House Bill 350 would do in year one, is not going to help this problem—it’s going to make it worse. And in doing so, it would ultimately make health care in Delaware more expensive—not less expensive. The key to lowering health care costs is to improve quality, access and equity Data show that about 5% of patients in the United States account for more than 50% of all health care costs. These are primarily patients who have complex and poorly managed chronic conditions that cause them to end up in the most expensive care settings—hospitals, operating rooms, emergency departments. The key to driving down health care costs is to improve quality and equity so that everyone is supported in achieving their best health, and these high users of the most expensive kinds of care are better supported in managing their health conditions such as diabetes or heart failure in the appropriate way. In doing so, they prevent the need for costly emergency or “rescue” care. Let’s do more—not less—of what we already know works Health care is not a one-size-fits-all industry. The delivery of care for patients across a diverse population requires multiple interventions at the same time. These interventions are designed not only to improve the quality of care but also to close the gap in terms of health care disparities. That’s important, because when we improve care and outcomes for the most vulnerable populations, we tend to get things right for everyone. One type of intervention is about doing exactly the right things for a patient based on the evidence of what will help—and doing nothing extra that will cause harm or generate additional costs without providing additional benefit. An example of this might be ensuring that every patient who has a heart attack gets a certain drug called a beta blocker right after their heart attack, and they receive clear guidance and support on the actions they must take to reduce their risk of a second heart attack, such as regular exercise and good nutrition. The second type of intervention is for the highest-risk populations. These are patients who live in poor communities where there are no gyms and no grocery stores, and people commonly have challenges with transportation and lack of access to resources that makes it difficult—sometimes impossible—to follow their plan for follow-up care. They lack access to high-nutrient food that reduces their risk of a second heart attack. They also live in areas where there are fewer health care providers compared to more affluent areas. These interventions tend to be very intensive and do not generate income for health systems; in fact, they require significant non-reimbursed investment, but they are necessary to keep our most vulnerable patients healthy. The medical community has developed interventions for these populations that are proven to work. A local example is the Delaware Food Pharmacy program, which connects at-risk patients with healthy food and supports their ability to prepare it. The program helps patients improve their overall health and effectively manage their chronic conditions so they can prevent an adverse event that would put them back in the hospital or emergency department. When we work together, we succeed We’ve seen incredible examples of how this work can be successful right here in Delaware. Delaware was the first state in the country to eliminate a racial disparity in colorectal cancer, and we did this by expanding cancer services, including making it easy for vulnerable people to get preventive cancer care and screenings. This is an incredible success story that continues to this day, and it was the result of thoughtful, detail-oriented partnerships among the state and the health care community. The work continues as we collaborate to reduce the impact and mortality of breast cancer in our state. Unfortunately, these kinds of interventions are the first thing to go when health care budgets get slashed, because they don’t generate revenue and are not self-sustaining. These kinds of activities need to be funded—either through grants or an external funder, or by the hospitals and health care systems. By narrowly focusing on cost, we risk losing the progress we have made Delaware House Bill 350, as it’s proposed, would cause harm in two ways: First, it would compromise our ability to invest in these kinds of interventions that work. Second, it increases the risk that higher-cost health services and programs that are disproportionately needed by people in vulnerable communities could become no longer available in Delaware. In states where the government has intervened in the name of cutting costs, like Vermont and Massachusetts, we see the consequences–less quality and reduced equitable access to much-needed services. House Bill 350 will widen the gap between those who have means and those who are more vulnerable. These changes will lead to increased disease burden on these populations. They will end up in the emergency room more and hospitalized more, which is by far the most expensive kind of care. That’s not what anyone wants—and it’s the opposite of what this bill was intended to accomplish. At this moment, in Delaware, we have an opportunity to put our state on a sustainable path to better health for all Delawareans. House Bill 350 is not that path. However, the discussion that House Bill 350 has started is something that we can build on by bringing together the stakeholders we need to collaborate with to solve these complicated problems. That includes Delaware’s government and legislators, the hospitals and health centers, the insurance, pharmacy and medical device industries, and most importantly, patients and the doctors who care for them. LeRoi Hicks, M.D., is the campus executive director for ChristianaCare, Wilmington Campus.

View all posts