Understanding Polyps and Their Colorectal Cancer Counterparts
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Researchers from Vanderbilt University have discovered how polyps develop into colorectal cancer. This knowledge could help to improve how this type of cancer is monitored and treated. The study was published in Cell.
Colorectal cancers arise from precursor polyps
The researchers created a multiomic atlas of the two most common colorectal polyps in humans – conventional adenomas and serrated polyps – and their colorectal cancer counterparts.
Previous studies indicate that conventional adenomas accumulate gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes, resulting in the formation of microsatellite stable (MSS) colorectal cancers. Sessile serrated lesions, on the other hand, resemble hypermutated MSI-high (MSI-H) colorectal cancers and are distinct from conventional adenomas (i.e., tumor development isn’t initiated by disruptions to the adenomatous polyposis col APC gene.)
MSS versus MSI
Microsatellite instability (MSI) results from compromised DNA mismatch repair and is a measure of a tumor’s instability. Colorectal cancers are often given an “MSI status”, meaning they will be either MSI or MSS – they will not be both. Tumors with a high-level of microsatellite instability are termed MSI-H. Microsatellite stable (MSS) tumors are deemed one of the most highly mutated types of tumor. These tumors often have poor immune cell infiltration.
Armed with this knowledge, the Cell study set out to identify and functionally validate distinct origins and molecular processes involved in the development of colorectal cancer.
Serrated polyps and adenomas have distinct cellular origins
One of the study’s corresponding authors, Dr. Martha Shrubsole, research professor in epidemiology at Vanderbilt University Medical Center considers the two types of polyp in more detail: “Conventional adenomas are the most common precancerous lesion in the colon. About one in four or five adults will have a conventional adenoma. These polyps are characterized by mutations in the APC gene, which activate the WNT pathway. They accumulate mutations in other genes, and we saw a very high stem potential in these polyps.”However, Shrubsole notes that serrated polyps typically do not possess APC mutations. Instead, they are characterized by epigenetic disruptions. The team reported that these disruptions are likely the result of injury and may originate from differentiated cells.
Shrubsole continues, “About 15–20% of people with polyps have a serrated polyp. A small proportion of both types of polyps may have the potential to develop into cancer and the development of polyps into cancer arises from an accumulation of mutations in cancer-driving genes. A variety of factors can influence this process, including lifestyle, diet and the microbiota.”
Malignant progression of colorectal polyps
The study was designed to include participants who were diverse in age, sex and race to ensure inclusion across many sociodemographic characteristics.
“Participants ranged in age from 46 to 74 years, including 41% female, 59% male, 21% Black, 2% Asian, 2% Hispanic and 71% White participants,” says Shrubsole. She notes that while the researchers haven’t yet tested for biological differences based on these characteristics, the team intends to focus on these factors with a larger cohort of participants.
The researchers analyzed 62 tumor tissue samples using a variety of techniques including single-cell transcriptomics, genomics and immunohistopathology. While each of these approaches provides an important perspective into the understanding of carcinogenesis processes in polyps, when used in isolation, the data they generate is limited for the context of this study.
Dr. Robert Coffey, Jr., Ingram Professor of Cancer Research at Vanderbilt University Medical Center explains that using a combination of approaches “can provide a fuller picture and is how we will make significant advances in understanding the tumorigenic process in human specimens.”
He continues, “For example, using single-cell transcriptomics, we identified expression patterns that occurred within individual cells to identify cell characteristics unique to different polyps. We could then use genomics to evaluate whether the mutational patterns were related to these polyps and immunohistopathology to observe the spatial pattern of expression across the polyp.”
Mapping microbiota-related events to epigenetic alterations in cancer cells
The researchers observed a transcriptional signature in serrated polyp-specific cells that implicate a damage response to microbiota. Lau elaborates on the role the microbiota may plays in terms of damage and initiating a metaplastic cascade: “Work by Dr. Cynthia Sears at Johns Hopkins University has also shown microbes are important in serrated tumorigenesis in murine mono-association studies. Microbial biofilms are present on up to 90% of right-sided colorectal cancer, which are enriched for serrated tumors. Metaplastic cells are also observed rarely in normal colonic mucosa, but their numbers increase in situations of dysbiosis such as inflammatory bowel disease.”
Lau and colleagues are currently attempting to map the events connecting the microbiota to epigenetic alterations in tumor cells.
Identifying key gene programs and pathways
The team discovered that in the serrated-polyp specific cells, genes were highly expressed that are not normally found in the colon. Specifically, these cells began expressing genes typically found in the upper gastrointestinal tract and other endodermal organs.
Another of the study’s corresponding authors, Dr. Ken Lau, associate professor of cell and developmental biology at Vanderbilt University Medical Center highlights the four genes, which are summarized below.
- MUC5AC is a gene related to the production of mucin glycoproteins in the gastric epithelium, typically found in the pit structures of the stomach. MUC5AC is also a major mucus component of the airways.
- MSLN is a protein-coding gene typically found in mesothelial tissue consisting of squamous cells.
- AQP5 encodes an aquaporin, or water channel protein. Native expression of this gene is found in salivary and tear glands affecting water homeostasis, as well as deep antral gland mucous cells and antral stem/progenitor cells in the distal stomach.
- CDX2 regulates the transcription of several genes expressed in the intestinal epithelium. As described by Dr. Eric Fearon and co-workers, its loss destabilizes colonic identity.”
Issues with over- and under-surveillance
According to Coffey “there is a problem with both over- and under-surveillance of individuals who have been diagnosed with polyps”. Over-surveillance can be an issue because some individuals may never have another polyp, meaning they may not require frequent surveillance, and it could be possible to delay a surveillance procedure. At the other end of the spectrum, under-surveillance can result in some individuals developing cancer before their next scheduled examination.
“Surveillance intervals have been based on the size, number and histopathological features of polyps for decades. The next frontier is to better classify who needs a repeat colonoscopy now, later or never. Not only will this be better for the patient in avoiding needless procedures, but it will also help to conserve health system resources,” says Coffey. “We believe that biomarkers to further classify the behavior of polyps will be key to improving surveillance as well as to informing new treatment approaches.”
The authors suggest that staining for the presence of MUC5AC and absence of CDX2 could greatly aid establishing an accurate diagnosis of suspected sessile serrated polyps. This, in turn, would then enable appropriate screening intervals to be determined for these lesions, versus conventional adenomas.
“Single-cell transcriptomics has identified a treasure trove of interesting genes in these two types of tumors, such as acquisition of markers of stemness in MSI-H colorectal cancers, that may be pursued as biomarkers or therapeutic targets,” concludes Coffey.
Reference: Chen B, Scurrah CR, McKinley ET, et al. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell. 2021;184(26):6262-6280.e26. doi: 10.1016/j.cell.2021.11.031
Robert Coffey, Martha Shrubsole and Ken Lau were speaking to Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.
