Abstract
Molecular alterations are not randomly distributed in colorectal cancer (CRC), but rather clustered on the basis of primary tumor location underlying the importance of colorectal cancer sidedness. We aimed to investigate whether circulating tumor cells (CTC) characterization might help clarify how different the patterns of dissemination might be relative to the behavior of left- (LCC) compared to right-sided (RCC) cancers. We retrospectively analyzed patients with metastatic CRC who had undergone standard baseline CTC evaluation before starting any first-line systemic treatment. Enumeration of CTC in left- and right-sided tumors were compared. The highest prognostic impact was exerted by CTC in left-sided primary cancer patients, even though the lowest median number of cells was detected in this subgroup of patients. CTC exhibit phenotypic heterogeneity, with a predominant mesenchymal phenotype found in CTC from distal compared to proximal primary tumors. Most CTC in RCC patients exhibited an apoptotic pattern. CTC in left-sided colon cancer patients exhibit a predominant mesenchymal phenotype. This might imply a substantial difference in the biology of proximal and distal cancers, associated with different patterns of tumor cells dissemination. The poor prognosis of right-sided CRC is not determined by the hematogenous dissemination of tumor cells, which appears to be predominantly a passive shedding of non-viable cells. Conversely, the subgroup of poor-prognosis left-sided CRC is reliably identified by the presence of mesenchymal CTC.
Highlights
There is discrepancy between the latest advances in molecular segmentation of colorectal cancer (CRC), which recently led to the consensus molecular subtyping of the disease, and the insufficient availability of biomarkers ready for routine clinical use [1]
This might explain the different pattern of response to biological agents, with left-sided colorectal cancer (LCC) more prone to respond to anti-EGFR therapies and right-sided colorectal cancer (RCC) more responsive to antiangiogenic drugs
Mesenchymal-Like right right right right right right right left left left left left left left left left rectum rectum rectum rectum rectum rectum rectum rectum. This is the first publication reporting on the detection rate and the prognostic significance of circulating tumor cells (CTC) according to primary tumor sidedness in metastatic colorectal cancer patients
Summary
There is discrepancy between the latest advances in molecular segmentation of colorectal cancer (CRC), which recently led to the consensus molecular subtyping of the disease, and the insufficient availability of biomarkers ready for routine clinical use [1]. Prominent differences have been demonstrated in terms of tumor microenvironment, which results to be inflamed and with marked stromal infiltration in left cancers as compared to right cancers, which in turn are characterized by lower inflammatory status and higher expression of pro-angiogenic factors. This might explain the different pattern of response to biological agents, with left-sided colorectal cancer (LCC) more prone to respond to anti-EGFR therapies and right-sided colorectal cancer (RCC) more responsive to antiangiogenic drugs. The secondary aim was to investigate whether CTC isolated from proximal and distal colorectal cancers might differ in their biological features, referring to epithelial-mesenchymal transition (EMT)-related phenotype
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