Radiation induces epithelial-mesenchymal transition in colorectal cancer cells

Abstract

Abstract. Radiotherapy remains a major approach to adjuvant therapy for patients with advanced rectal cancer. Nevertheless, the effects of radiation on malignant processes have yet to be clarified. The aim of this study was to assess the biological effects of radiation on colorectal cancer (CRC) cells with special reference to epithelial-mesenchymal transition (EMT), a key developmental program often activated during cancer invasion and metastasis. We investigated the effect of radiation on two colorectal cancer cell lines, CaR1 and DLD1, assessing cell morphology, motility, migration and invasive ability. Expression of molecules associated with EMT was determined using RT-PCR, Western blotting, and immunofluorescence staining in control and irradiated cells. We also used real-time RT-PCR to examine the expression of molecules associated with EMT before and after chemoradiotherapy. Thus, we studied 26 rectal cancer patients who received preoperative chemoradiotherapy followed by radical surgery. In addition, we examined the relationship between disease recurrence and the expression of a number of proteins. Irradiation caused CRC cells to undergo phenotypic changes characteristic of EMT: spindle-cell shape, loss of polarity, intercellular separation and pseudopodia formation. Irradiation enhanced cell migration and invasiveness. In irradiated CRC cells, molecular changes consistent with EMT were observed. In clinical samples, we observed molecular changes consistent with EMT, and those changes were significantly enhanced in patients with recurring disease. These results indicate that irradiation induces an alteration to a malignant phenotype consistent with EMT in colorectal cancer cells.

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

“…[40][41][42][43][44][45][46][47][48][49][50][51][52] Ionizing radiation can promote traits of EMT in normal human mammary epithelium, 41 lung carcinoma 42,43 and colorectal cancer cells. 44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT. 47,48 Snail enhances resistance to apoptosis by activating the PI3K/Akt and Erk1/2 pathways, 28 consistent with our data showing increased radiosensitivity after inhibition of PI3K/Atk and Erk1/2 and downregulation of Snail.…”

Epithelial–mesenchymal plasticity in carcinoma metastasis

“…Studies using colorectal cell lines have shown that expression of EMT inducers Snail1 or TGF-b in SMAD4-null cells increased resistance to chemotherapy (Hoshino et al 2009;Papageorgis et al 2011). Conversely, colorectal cell lines that were rendered oxaliplatin-resistant showed phenotypic and gene expression changes consistent with EMT (Yang et al 2006;Kawamoto et al 2012). Interestingly, tumor specimens taken from patients who had received 1 wk of preoperative chemotherapy prior to surgery resection displayed a more mesenchymal gene signature compared with prechemotherapy biopsy samples.…”

“…Interestingly, tumor specimens taken from patients who had received 1 wk of preoperative chemotherapy prior to surgery resection displayed a more mesenchymal gene signature compared with prechemotherapy biopsy samples. Furthermore, recurrent tumors frequently exhibited an EMT gene signature (e.g., decreased E-cadherin and increased vimentin) (Kawamoto et al 2012). Shintani et al (2011) found that, in non-small-cell lung carcinoma (NSCLC) patients, tumor biopsy prior to chemotherapy treatment showed epithelial markers but that this phenotype shifted toward mesenchymal markers following treatment.…”

Rhamnetin and Cirsiliol Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition (EMT) by miR-34a-mediated Suppression of Notch-1 Expression in Non-small Cell Lung Cancer Cell Lines

“…During cancer progression, tumor cells become more invasive after undergoing EMT and gain access to blood vessels through intravasation resulting in distant metastasis, the major cause of death from cancer (22). Several factors have been shown to induce EMT in vitro and in vivo, including hypoxia, reactive oxygen species, transforming growth factor ␤1, and radiation (23)(24)(25). Radiation elicits cell behaviors that are strongly associated with epithelial cancer such as differentiation dysregulation, genomic instability, phenotypic transition such as EMT, and aberrant multicellular organization (26,27).…”