Novel differentiation induction therapy for colorectal cancer by targeting to CEACAM1

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Carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1) is known to be downregulated at the transcriptional level in adenoma and carcinoma. Recent reports have shown that CEACAM1 is overexpressed at protein level in colorectal cancer, and correlated with clinical stage. The reason why colorectal cancer cells re-expressed CEACAM1 remains unclear. The aim of the present study was to clarify the implication of CEACAM1 re-expression in colorectal cancer. Immunohistochemical analyses were conducted with CEACAM1 long (CEACAM1-L) or short (CEACAM1-S) cytoplasmic domain-specific antibodies on clinical samples from 164 patients with colorectal cancer. The risk factors for metastasis and survival were calculated for clinical implication of CEACAM1 re-expression. Invasion chamber and wound healing assays were performed for the effect of CEACAM1 expression on invasion and migration of colorectal cancer cells. CEACAM1-L and CEACAM1-S stained with greater intensity at the invasion front t … More han at the luminal surface of tumors. Differences between the long and short cytoplasmic isoform expression levels were observed at the invasion front. Multivariate analysis showed that CEACAM1-L dominance was an independent risk factor for lymph node metastasis, hematogenous metastasis, and short survival. The Kaplan-Meier evaluation demonstrated that CEACAM1-L dominance was associated with shorter survival time (p<0.0001). In the invasion chamber and wound healing assays, CEACAM1-L promoted invasion and migration. Re-expression of CEACAM1 is observed at the invasion front of colorectal cancer. CEACAM1-L dominance is associated with metastasis and shorter survival of the patients with colorectal cancer. CEACAM1-L dominance is important for colorectal cancer cells invasion and migration. Tumor budding formed by histological undifferentiated cancer cells beyond the border of tumor margin is associated with lymph node metastasis. However, cancer nests with a hollow, conceivable histological advanced phenotype of tumor budding, has not been discussed. Next we investigate that the appearance "spheroid with a hollow (SWH)" exists beyond the border of the invasive margin, and associates with metastases and prognosis. Moreover, we present that CEACAM1 isoform balance is associated with SWH formation. Immunohistochemical analyses with CEACAM1 and M30 as an apoptosis marker were performed, to address CEACAM1 expression of SWH and central cells apoptosis for SWH formation. The correlations between the SWH beyond the border of the invasive margin and clinicopathological characteristics of 314 patients with colorectal cancer were evaluated. Three dimensional (3D) culture was conducted with colorectal cancer cells transfected with CEACAM1 cDNA or shRNA, to evaluate that CEACAM1 isoform balance controls colorectal SWH formation. The existence of SWH formation accompanying the central cells apoptosis was confirmed by M30 staining and serial section with CEACAM1 staining. Of the 314 patients, 96 (30.4%) were classified as having SWH. SWH is an independent risk factor for metastases and shorter survival. In 3D culture, CEACAM1 isoform balance modulated SWH formation of colorectal cancer cells.The colorectal cancer SWH beyond the border of tumor margin is more important for prediction of malignant potential than tumor budding. Less