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Presence of twist1-positive neoplastic cells in the stroma of chromosome-unstable colorectal tumors


Celesti, Giuseppe; Di Caro, Giuseppe; Bianchi, Paolo; Grizzi, Fabio; Basso, Gianluca; Marchesi, Federica; Doni, Andrea; Marra, Giancarlo; Roncalli, Massimo; Mantovani, Alberto; Malesci, Alberto; Laghi, Luigi (2013). Presence of twist1-positive neoplastic cells in the stroma of chromosome-unstable colorectal tumors. Gastroenterology, 145(3):647-657.e15.

Abstract

BACKGROUND & AIMS: Cancer cells undergo an epithelial-to-mesenchymal transition (EMT) to become invasive, allowing tumors to progress. However, there is no direct evidence that human cancer cells undergo an EMT. In mouse cancer cells, up-regulation of transcription factor Twist1 was shown to promote an EMT. We searched the stroma of human colorectal tumor samples for TWIST1-positive cells with a mesenchymal phenotype and neoplastic genotype. METHODS: We measured the expression of TWIST1 in human colorectal cancer (CRC) cell lines and examined the effects of overexpression or knockdown in vitro and in mice. We used immunohistochemistry to measure levels of TWIST1 in 201 colorectal tumor samples. In 20 samples, immunostaining was combined with fluorescence in situ hybridization analyses. Levels of TWIST1 messenger RNA (mRNA) were measured in blood samples from 15 patients. RESULTS: TWIST1 was required to maintain the mesenchymal phenotype and invasiveness of the microsatellite-stable CoLo741 cells (which express endogenous TWIST1) and SW480 (expressing transgenic TWIST1). TWIST1 mRNA was not translated in CRC cells with microsatellite instability (HCT116). Syngenic TWIST1-positive colon carcinoma cells (CT26) that invaded tissues surrounding tumors acquired a mesenchymal phenotype. The presence of TWIST1-positive cells in the stroma of human colorectal tumors correlated with microsatellite stability (P = .05), stage IV cancer (P = .02), and disease-free survival time (P < .01). Trisomies of chromosome 7 and/or chromosome 20 were detected in 17 of 20 colorectal tumor samples, each of which contained TWIST1-positive cells with matching chromosomal gains in the tumor stroma (86 of 776 counted cells; 11.1%). No trisomy was observed in TWIST1-negative stromal cells (0 of 1249 cells; P < .001). Levels of TWIST1 mRNA were significantly higher in blood samples from patients with CRC than controls. CONCLUSIONS: The stroma of human colorectal tumors contains TWIST1-positive cancer cells with mesenchymal phenotypes. Patients with CRC have higher levels of TWIST1 mRNA than healthy individuals.

Abstract

BACKGROUND & AIMS: Cancer cells undergo an epithelial-to-mesenchymal transition (EMT) to become invasive, allowing tumors to progress. However, there is no direct evidence that human cancer cells undergo an EMT. In mouse cancer cells, up-regulation of transcription factor Twist1 was shown to promote an EMT. We searched the stroma of human colorectal tumor samples for TWIST1-positive cells with a mesenchymal phenotype and neoplastic genotype. METHODS: We measured the expression of TWIST1 in human colorectal cancer (CRC) cell lines and examined the effects of overexpression or knockdown in vitro and in mice. We used immunohistochemistry to measure levels of TWIST1 in 201 colorectal tumor samples. In 20 samples, immunostaining was combined with fluorescence in situ hybridization analyses. Levels of TWIST1 messenger RNA (mRNA) were measured in blood samples from 15 patients. RESULTS: TWIST1 was required to maintain the mesenchymal phenotype and invasiveness of the microsatellite-stable CoLo741 cells (which express endogenous TWIST1) and SW480 (expressing transgenic TWIST1). TWIST1 mRNA was not translated in CRC cells with microsatellite instability (HCT116). Syngenic TWIST1-positive colon carcinoma cells (CT26) that invaded tissues surrounding tumors acquired a mesenchymal phenotype. The presence of TWIST1-positive cells in the stroma of human colorectal tumors correlated with microsatellite stability (P = .05), stage IV cancer (P = .02), and disease-free survival time (P < .01). Trisomies of chromosome 7 and/or chromosome 20 were detected in 17 of 20 colorectal tumor samples, each of which contained TWIST1-positive cells with matching chromosomal gains in the tumor stroma (86 of 776 counted cells; 11.1%). No trisomy was observed in TWIST1-negative stromal cells (0 of 1249 cells; P < .001). Levels of TWIST1 mRNA were significantly higher in blood samples from patients with CRC than controls. CONCLUSIONS: The stroma of human colorectal tumors contains TWIST1-positive cancer cells with mesenchymal phenotypes. Patients with CRC have higher levels of TWIST1 mRNA than healthy individuals.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:25 Sep 2013 15:34
Last Modified:07 Dec 2017 22:40
Publisher:Elsevier
ISSN:0016-5085
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1053/j.gastro.2013.05.011
PubMed ID:23684708

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