The rapid rise of colorectal cancer in younger people remains perplexing, but a new study fills in a missing piece of the puzzle.
Researchers found that three genes involved in immunity and inflammation are more active in and around tumors in early onset colorectal cancer. Experiments showed how these upregulated genes interact with other genes to reshape the immune environment for colorectal cancer.
“Our findings suggests that the immune system in younger patients is actually failing at mounting a good response against these tumors,” said senior author Sudarshan Anand, Ph.D., of Oregon Health & Science University.
“It was a major surprise,” he said. “Usually we think immune responses decrease with age. But here, we find the opposite – patients who are younger seem to have an immune system that is not recognizing or killing the tumor cells.” Anand is an associate professor of cell, developmental and cancer biology in the OHSU School of Medicine.
While the rate of colorectal cancer has plummeted in older populations, the cancer has more than doubled since the 1990s among those younger than 50. The causes are unclear, but scientists pursuing answers strongly suspect three related factors: diet, bacteria in the gut, and inflammation.
The OHSU researchers, including surgeon Liana Tsikitis, M.D., and surgical resident Ivy Gardner, M.D., set out to explore differences in the tumor microenvironment, that is, nearby non-tumor cells and immune cells that penetrate tumors via blood vessels and lymphoid capillaries. They focused on immune differences between patients age 50 or younger and those 65 or older.
The Oregon Colorectal Cancer Registry gave them access to preserved tumor samples from patients along with detailed patient records including treatments received, pathology, gene mutations status, and outcomes. A paper describing the work appears in the journal ImmunoHorizons.
To explore gene activity, the researchers extracted RNA from the tumor tissue. RNA is the single-stranded mate of double-stranded DNA, and it carries the encoded messages from genes that direct the synthesis of proteins. Extracting and sequencing RNA reveals which genes were active at the moment the tumor tissue was removed and preserved.
They used technology that made it possible to simultaneously measure the activity of 770 immune response genes in preserved tumor samples. They compared gene activity in samples from 40 early-onset patients with that in samples from 39 late onset patients.
The three genes found to be more active in early onset tumors – C7, CFD and SAA1 – are all associated with infection and inflammation. C7 and CFD are proteins involved in an immune process called complement activation, crucial for defense from microbial infections and for clearance of cellular debris. SAA1 plays a signaling role in the inflammation response to injury and infection.
The activity of the three genes appeared to make a difference in patient outcomes. With increased activity of CFD and SAA1, cancers progressed sooner after treatment. Increased activity of C7 correlated with worse overall survival.
Digging deeper, the researchers engineered tumor cells to express the CFD and SAA1 genes, and implanted these tumor cells in mice. Tumors with high SAA1 expression had similar growth rates as the tumors with low SAA1 expression, but CFD-expressing tumors had higher volumes compared with controls. CFD also triggered changes in the activity of other genes, and the pattern of activity correlated with what is seen in tumor samples from people with early onset colorectal cancer.
The findings paradoxically suggest that early onset colorectal cancer is associated with an inflammatory state that would be more expected in an older population. The researchers said it may be that early onset disease is preceded by the early onset of low-grade inflammation, which leads to a tumor-permissive microenvironment. They caution, however, that it remains unknown whether the increased expression of CFD, C7, and SAA1 in early onset cases is the result of underlying immune dysregulation or the result of an inappropriate immune response to cancer.
“This is one of those things that is very hard to tease out, even with animal models,” Anand said.
The researchers believe that the immune signatures they found in patient samples may have been shaped by interactions with the microbiome, the microbes that live in the intestinal tract. Anand said his team is focusing on understating the microbiome connection, whether it is composed differently in early onset patients, and if there is a correlation between the microbiome composition and the genes with boosted activity in early onset samples.
Manipulation of the microbiome – by diet alterations, probiotics, antibiotics, or fecal transplant – is already under study as a potential way to improve response to cancer treatments. These new findings add evidence that this strategy could be well suited to people with early onset colorectal cancer.
A Distinct Innate Immune Signature of Early Onset Colorectal Cancer by Ivy H. Gardner, Ragavan Siddharthan, Katherine Watson, Elizabeth Dewey, Rebecca Ruhl, Sokchea Khou, Xiangnan Guan, Zheng Xia, V. Liana Tsikitis and Sudarshan Anand. ImmunoHorizons (June 23, 2021)
Why Is Colorectal Cancer Rising Rapidly among Young Adults? by NCI staff. Cancer Currents (Nov. 5, 2020)