Young-Onset Colorectal Cancer Tumors Hold More Stromal Cells, a Feature Tied to Chemo Resistance in Other Cancers

Colorectal tumors from younger patients contain a larger share of connective and supporting cells, known as stromal cells, than tumors from older patients, according to a study published Oct. 29 in Nature Medicine. In other solid cancers, a high proportion of these cells has been linked to resistance to chemotherapy, researchers at Dana-Farber Cancer Institute and their partners said.

The study offers a detailed look at how colorectal cancer in people under 50 may differ at the cellular level. It does not show that younger patients' tumors respond worse to chemotherapy, and it does not change how anyone is treated today.

For the growing number of adults in their 30s and 40s facing this diagnosis, the study matters as a direction for research. Colorectal cancer is now the leading cause of cancer death in Americans under 50 for men and women combined, according to the American Cancer Society, although breast cancer remains the leading cause among women in that age group. Doctors still do not know why rates in younger adults keep climbing.

Inside 850,000 Tumor Cells

The team, from Dana-Farber, Mass General Brigham's Gene Lay Institute of Immunology and Inflammation, and the Broad Institute, studied 189 tumors removed during surgery at Brigham and Women's Hospital in Boston and stored in Dana-Farber's Gastrointestinal Biobank. Fifty-four came from patients diagnosed before age 50 and 135 from patients 50 or older, with ages ranging from 29 to over 90.

Using a technique called single-nucleus RNA sequencing, the researchers measured gene activity in more than 850,000 individual cells. Rather than simply splitting patients into "young" and "old" groups, they looked for features that changed gradually with age, adjusting for tumor location, stage, sex, and prior treatment.

In tumors of the most common colorectal cancer subtype, younger patients had a significantly higher proportion of stromal cells relative to cancer cells. The team confirmed the pattern using gene activity data from 564 other tumors and computer analysis of stained tissue images from 712 tumors.

The study found other differences, too. Younger patients' cancer cells showed higher activity of long non-coding RNAs, many with unknown functions, along with gene activity suggesting stronger cell signaling that could help cancer cells invade nearby tissue.

"By looking beyond conventional age cutoffs, we've uncovered biological patterns that earlier studies may have missed," said co-senior author Ana C. Anderson, Ph.D., of the Gene Lay Institute.

Stromal Cells and the Chemotherapy Question

Stromal cells form the structural neighborhood around a tumor. They are not cancer cells, but they can shape how a tumor grows, how it interacts with the immune system, and how well drugs reach the cancer.

That is why the finding drew attention. Still, the researchers did not test whether these tumors resisted chemotherapy. The link comes from earlier studies of other solid cancers. For colorectal cancer in younger adults, it remains a hypothesis to test.

"It gives a huge amount of hope," co-senior author Dr. Kimmie Ng, director of Dana-Farber's Young-Onset Colorectal Cancer Center, told The Boston Globe. "It really serves as a guidepost to where we should direct our future research efforts."

Dr. John Paul Shen, an associate professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center who was not involved in the study, told the Globe the work gives scientists access to large amounts of detailed data. "There's some very clear experiments that we might do in our lab or other people would do in their labs around the world," he said. Shen and other experts also noted that the dataset, while expansive at the cellular level, comes from a limited number of people.

Evidence Check: A Detailed Map, Not a New Treatment

This was a descriptive study of surgically removed tissue. It shows that certain features are more common in younger patients' tumors, but it does not prove that those features cause more aggressive disease, the researchers said.

Because the methods captured relatively few immune cells, the study could not answer how immune responses differ by age. All core samples came from one Boston hospital, although Ng told the Globe that the study's patient group aligns with what is generally known about young-onset colorectal cancer patients around the world. The work was funded in part by the National Institutes of Health, the American Cancer Society, and several foundations.

Current treatment guidelines are unchanged. The findings are not a reason for patients to change their chemotherapy plans, but patients under 50 can ask their oncologist whether clinical trials for young-onset disease are available.

Future work will examine how these cellular changes affect cancer growth and spread, and how the cell programs interact with chemicals from the diet and with gut microbes, according to Dana-Farber. Experts also said the findings should be tested in other patient groups.

Symptoms Younger Adults Should Not Dismiss

The research arrives as diagnoses climb. Colorectal cancer rates among people under 50 rose 2.9% per year from 2013 through 2022, according to American Cancer Society data cited by Dana-Farber, and younger patients are often diagnosed at a later stage.

Delays are part of the problem. One Stanford Medicine study found that younger patients take 40% longer to be diagnosed than older patients, and nearly three in four patients under 50 have advanced disease by the time they are diagnosed, according to Stanford Medicine.

Warning signs include blood in the stool or rectal bleeding, dark or tarry stools, regular abdominal pain or bloating, and changes in bowel habits or stool consistency, according to Mayo Clinic. Unintended weight loss, fatigue, and anemia (a low red blood cell count) are also possible signs of colorectal cancer, according to the American Cancer Society. These symptoms often have other causes, such as hemorrhoids or irritable bowel syndrome, but they deserve prompt evaluation at any age.

The U.S. Preventive Services Task Force recommends screening starting at 45 for adults at average risk. People with a parent or sibling who had colorectal cancer or advanced polyps, or with conditions such as ulcerative colitis or Crohn's disease, may need to start earlier. Colonoscopy is the most common screening test, and stool-based tests are a less invasive option. A positive stool test should be followed by a colonoscopy.

Key Questions Answered

What did the Dana-Farber study find? In the most common colorectal cancer subtype, tumors from younger patients had a higher share of stromal, or supporting, cells. Younger patients' tumors also showed other distinct patterns of gene activity.

Does this mean chemotherapy works less well in younger patients? Not necessarily. The study did not test chemotherapy response. The link to chemotherapy resistance comes from research in other solid cancers.

How large was the study? It analyzed 189 tumors and more than 850,000 cells, then checked the main finding in hundreds of additional tumors.

Does this change treatment? No. Current treatment and screening guidelines remain the same.

What symptoms should younger adults watch for? Rectal bleeding or blood in the stool, dark stools, ongoing abdominal pain or bloating, changes in bowel habits, unintended weight loss, fatigue, and anemia.

When should screening start? At 45 for average-risk adults, and possibly earlier for people with a family history of colorectal cancer or certain inflammatory bowel diseases.

Published by Medicaldaily.com