Patients whose stage 2 colon cancer tested negative for CDX2 expression (left) had a worse prognosis than those whose cancer tested positive (right).
Image credit: Lab of Piero Dalerba/CUMC
The multicenter team – including members from Columbia University Medical Center (CUMC), New York, NY – describes the discovery in the New England Journal of Medicine.
Colon cancer is cancer that starts in the colon or large intestine – the last stage of digestion. As the cancer progresses, it triggers metastasis – where migratory cancer cells break away, travel through the lymphatic system and set up secondary tumors in other parts of the body. Metastatic tumors are the major cause of death from cancer.
Stage 2 colon cancer is where the cancer has spread through the wall of the colon and may have invaded nearby tissue or organs, but has not yet reached nearby lymph nodes. In the majority of cases, surgery alone is enough to cure the cancer – that is, remove all the cancerous tissue. However, in about 15-20% of cases, the patients eventually relapse and die of metastatic disease.
First author Piero Dalerba, an assistant professor of medicine, pathology and cell biology at CUMC, says:
“The problem is that we don’t have an easy way to single out these patients before they relapse and accurately predict who could benefit from post-surgical, or adjuvant, chemotherapy.”
Other studies have found biomarkers that can predict which stage 2 colon cancer patients are most likely to relapse after surgery, but none have yet found a biomarker that predicts which patients in this group are also likely to benefit from post-surgery chemotherapy.
Researchers looked for potential biomarkers in cancer stem cells
Usually, when screening for potential biomarkers in cancer, researchers look at gene expression patterns in tumor cells. But for their study, Prof. Dalerba and colleagues turned to cancer stem cells instead.
The idea of cancer stem cells is quite recent in cancer research. For example, in 2012, three different teams published papers proposing that a restricted cell population appears to be the source of new tumor cells – in much the same way as stem cells are the source of mature, differentiated healthy cells.
Senior author Prof. Michael F. Clarke, early pioneer of the idea of cancer stem cells, who among other things heads a lab in Stanford University’s Ludwig Center for cancer stem cell research, explains why they turned to cancer stem cells:
“We reasoned that tumors containing high numbers of cancer stem cells might be associated with a more aggressive disease and wanted to find a way to easily find them.”
Using a new bioinformatics approach, the team searched data from over 2,000 colon cancer patients and found 16 genes whose lack of expression is always tied to high levels of cancer stem cell markers.
Of the 16 potential biomarkers, they found only one – the gene CDX2 – for which a standardized test that detects its expression is already available.
CDX2 regulates cell differentiation – that is, deciding the type of cell an immature stem cell matures into – in the lining of the colon, which is where colon cancer starts.
The team found that colon cancer patients whose tumors did not express CDX2 were more likely to relapse and die, compared with patients whose tumors did express CDX2.
The researchers were surprised by the finding, as Prof. Dalerba explains:
“We wanted to understand if the small group lacking CDX2 expression – approximately 4% of the global colon cancer population – fared poorly because of an intrinsic resistance to chemotherapy. To our surprise, we found that, on the contrary, tumors lacking CDX2 expression, despite being very aggressive from a biological point of view, also appeared to benefit from early treatment with adjuvant chemotherapy.”
Further analysis using data from other projects showed that the finding was also true for stage 2 colon cancer patients; those whose tumors lacked CDX2 expression were more likely to benefit from post-surgery chemotherapy than counterparts whose tumors did express the gene.
Prof. Dalerba