Circulating Tumor Cells in Right- and Left-Sided Colorectal Cancer

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.

Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples

“…The concordance of the KRAS status between primary tumors and CTCs varies between 50% [26] and 77% [24], supporting the existence of different clones within primary mCRC. Additionally, CTCs from left-side mCRC more frequently display a mesenchymal phenotype coherent with EMT, while CTCs from right-side mCRC show an apoptotic morphology [27].…”

“…Although not validated in clinical practice, both the CTCs count and their characterization are being explored as tools for monitoring the evolution of metastatic cancers as well as their sensitivity to anti-neoplastic drugs. For example, the reduction of the number of CTCs during treatment is associated with lower probability of disease progression, and longer progression-free and overall survivals in HER2- [20] Discordance in HER2 status between primary and metastatic status influencing response to anticancer treatment [21] Prostate Cancer AR signaling modification upon hormonal treatments influences outcomes [22] Wnt activation leading to hormonal treatment failure [23] CTC heterogeneity as indicator for first line treatment [24] AR-V7 nuclear expression predicts better response to chemotherapy compared to AR signaling inhibitors [25] Colorectal Cancer 50% concordance in KRAS status between primary tumor and CTC as surrogate of spatial heterogeneity [26] Differential phenotype of CTC from right and left side may explain different metastasization patterns [27] Hepatocellular Cancer EMT of CTC relates with metastasization process [28] positive and HER2-negative mBC patients, but not in triple negative patients [32].…”

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

“…CTC heterogeneity has been shown and described in other tumor entities (21)(22)(23)(24). We also found a diverse population of CTC in a pilot study of 20 EAC patients undergoing multimodal treatment (14).…”

Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma

“…Many groups have confirmed the presence of heterogeneous CTC phenotypes (such as epithelial, epithelium–mesenchymal transition (EMT) and mesenchymal/stem) in patients with different cancers, including CRC [ 6 , 7 ]. Interestingly, immunoaffinity-dependant negative selection techniques demonstrated higher efficacy in isolating heterogeneous CTCs from the blood of patients with cancer [ 8 , 9 ].…”