2010 Fiscal Year Final Research Report
Novel differentiation induction therapy for colorectal cancer by targeting to CEACAM1
| Project/Area Number |
20591554
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Wakayama Medical University |
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Principal Investigator |
YOKOYAMA Shozo Wakayama Medical University, 医学部, 助教 (90398462)
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| Co-Investigator(Kenkyū-buntansha) |
HOTTA Tsukasa 和歌山県立医科大学, 医学部, 講師 (50244744)
TAKIFUJI Katsunari 和歌山県立医科大学, 医学部, 講師 (00254540)
MATSUDA Kenji 和歌山県立医科大学, 医学部, 助教 (30398458)
YAMAUE Hiroki 和歌山県立医科大学, 医学部, 教授 (20191190)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 実験外科学 |
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| Research Abstract |
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
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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
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[Journal Article] Re-expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer.2011
Author(s)
Ieda J, Yokoyama S, Tamura K, Takifuji K, Hotta T, Matsuda K, Oku Y, Nasu T, Kiriyama S, Yamamoto N, Nakamura Y, Shively JE, Yamaue H.
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Journal Title
Int J Cancer. (Epub ahead of print)
Pages: doi:10.1002/ijc.26072
Peer Reviewed
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[Presentation] CEACAM1 expressing spheroid with a hollow beyond the invasive margin indicates the malignant potential of colorectal cancer.2011
Author(s)
Shozo Yokoyama, Koichi Tamura, Junji Ieda, Shigehisa Kiriyama, Katsunari Takifuji, Tsukasa Hotta, Kenji Matsuda, Yoshimasa Oku, Toru Nasu, Naoyuki Yamamoto, John E. Shively, Hiroki Yamaue
Organizer
AACR 102nd Annual Meeting
Place of Presentation
Orlando
Year and Date
2011-04-06
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[Presentation] 大腸癌先進部のCEACAM1を発現する中空を伴う球体形成の臨床的意義2010
Author(s)
横山省三, 田村耕一, 家田淳司, 瀧藤克也, 堀田司, 松田健司, 奥喜全, 那須亨, 橋本忠通, 山本直之, 岩本博光, 山上裕機
Organizer
第23回日本バイオセラピィ学会
Place of Presentation
大阪
Year and Date
2010-12-10
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[Presentation] 大腸癌先進部における中空を伴う球体形成の臨床的意義2010
Author(s)
横山省三, 田村耕一, 家田淳司, 瀧藤克也, 堀田司, 松田健司, 奥喜全, 渡邉高士, 那須亨, 桐山茂久, 山本直之, John E. Shively, 山上裕機
Organizer
第69回日本癌学会総会
Place of Presentation
大阪
Year and Date
2010-09-22
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[Presentation] CEACAM1 and CD133 expressing Spheroid with hollow at the invasion front of colorectal cancer -Novel metastatic and tumor initiating phenotype-.2010
Author(s)
Shozo Yokoyama, Koichi Tamura, Junji Ieda, Shigehisa Kiriyama, Katsunari Takifuji, Tsukasa Hotta, Kenji Matsuda, Yoshimasa Oku, Takashi Watanabe, Toru Nasu, Naoyuki Yamamoto, John E. Shively, Hiroki Yamaue
Organizer
9^<th> International Conference of the Asian Clinical Oncology Society
Place of Presentation
Gifu
Year and Date
2010-08-25
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[Presentation] Spheroid with hollow induced by CEACAM1 at the invasion front of colorectal cancer indicates tumor initiating growth and malignant potential.2010
Author(s)
Shozo Yokoyama, Koichi Tamura, Junji Ieda, Shigehisa Kiriyama, Katsunari Takifuji, Tsukasa Hotta, Kenji Matsuda, Yoshimasa Oku, Takashi Watanabe, Toru Nasu, Naoyuki Yamamoto, John E. Shively, Hiroki Yamaue
Organizer
20^<th> Annual International CEA Symposium
Place of Presentation
Montreal, Canada
Year and Date
2010-08-11
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[Remarks] ホームページ等
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