Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma

Takahiro Yamanashi, Yukihiro Nakanishi, Gen Fujii, Yuri Akishima-Fukasawa, Yoshihiro Moriya, Yae Kanai, Masahiko Watanabe, Setsuo Hirohashi

Research output: Contribution to journalArticle

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Abstract

Objective: The microenvironment of cancer plays a critical role in its progression. However, the molecular features of cancer-associated fibroblasts (CAFs) are less well understood than those of cancer cells. We investigated the clinicopathological significance of podoplanin expression in stromal fibroblasts in patients with colorectal cancer (CRC). Methods: We selected podoplanin as an upregulated marker in CAF from a DNA microarray experiment. Consequently, podoplanin was identified as an upregulated gene. Immunohistochemical podoplanin expression was investigated at the National Cancer Center Hospital, Tokyo, Japan, in 120 patients with advanced CRC, and its clinicopathological significance was examined. The biological function of podoplanin expression was also assessed by a coculture invasion assay with CRC cell lines such as HCT116 and HCT15. Results: Podoplanin expression was exclusively confined to stromal fibroblasts and absent in tumor cells. Podoplanin is absent in normal stroma except for lymphatic vessels. Staining was considered positive when over 30% of the cancer stroma was stained. Positive podoplanin expression was significantly correlated with a more distal tumor localization (p = 0.013) and a shallower depth of tumor invasion (p = 0.011). Univariate analysis revealed that negative podoplanin expression in stromal fibroblasts was significantly associated with reduced disease-specific survival (p = 0.0017) and disease-free survival (p < 0.0001). Multivariate analysis revealed that negative podoplanin expression (p = 0.016) and lymph node metastasis (p = 0.027) were significantly associated with disease-free survival. CRC cell invasion was augmented by co-culture with CAFs that were treated with siRNA for podoplanin. Conclusions: Our results suggest that a positive podoplanin expression in stromal fibroblasts could have a protective role against CRC cell invasion and is a significant indicator of a good prognosis in patients with advanced CRC, supported by biological analysis showing that podoplanin expression in CAFs is associated with decreased CRC cell invasion.

Original languageEnglish
Pages (from-to)53-62
Number of pages10
JournalOncology
Volume77
Issue number1
DOIs
Publication statusPublished - 2009 Jul
Externally publishedYes

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Colorectal Neoplasms
Fibroblasts
Neoplasms
Coculture Techniques
Disease-Free Survival
Cancer Care Facilities
Lymphatic Vessels
Tumor Microenvironment
Tokyo
Oligonucleotide Array Sequence Analysis
Small Interfering RNA
Japan
Multivariate Analysis
Lymph Nodes
Staining and Labeling
Neoplasm Metastasis
Cell Line
Survival
Cancer-Associated Fibroblasts
Genes

Keywords

  • Clinicopathologic study
  • Colorectal cancer
  • Immunohistochemistry
  • Podoplanin
  • Prognosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yamanashi, T., Nakanishi, Y., Fujii, G., Akishima-Fukasawa, Y., Moriya, Y., Kanai, Y., ... Hirohashi, S. (2009). Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma. Oncology, 77(1), 53-62. https://doi.org/10.1159/000226112

Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma. / Yamanashi, Takahiro; Nakanishi, Yukihiro; Fujii, Gen; Akishima-Fukasawa, Yuri; Moriya, Yoshihiro; Kanai, Yae; Watanabe, Masahiko; Hirohashi, Setsuo.

In: Oncology, Vol. 77, No. 1, 07.2009, p. 53-62.

Research output: Contribution to journalArticle

Yamanashi, T, Nakanishi, Y, Fujii, G, Akishima-Fukasawa, Y, Moriya, Y, Kanai, Y, Watanabe, M & Hirohashi, S 2009, 'Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma', Oncology, vol. 77, no. 1, pp. 53-62. https://doi.org/10.1159/000226112
Yamanashi, Takahiro ; Nakanishi, Yukihiro ; Fujii, Gen ; Akishima-Fukasawa, Yuri ; Moriya, Yoshihiro ; Kanai, Yae ; Watanabe, Masahiko ; Hirohashi, Setsuo. / Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma. In: Oncology. 2009 ; Vol. 77, No. 1. pp. 53-62.
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AU - Moriya, Yoshihiro

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AB - Objective: The microenvironment of cancer plays a critical role in its progression. However, the molecular features of cancer-associated fibroblasts (CAFs) are less well understood than those of cancer cells. We investigated the clinicopathological significance of podoplanin expression in stromal fibroblasts in patients with colorectal cancer (CRC). Methods: We selected podoplanin as an upregulated marker in CAF from a DNA microarray experiment. Consequently, podoplanin was identified as an upregulated gene. Immunohistochemical podoplanin expression was investigated at the National Cancer Center Hospital, Tokyo, Japan, in 120 patients with advanced CRC, and its clinicopathological significance was examined. The biological function of podoplanin expression was also assessed by a coculture invasion assay with CRC cell lines such as HCT116 and HCT15. Results: Podoplanin expression was exclusively confined to stromal fibroblasts and absent in tumor cells. Podoplanin is absent in normal stroma except for lymphatic vessels. Staining was considered positive when over 30% of the cancer stroma was stained. Positive podoplanin expression was significantly correlated with a more distal tumor localization (p = 0.013) and a shallower depth of tumor invasion (p = 0.011). Univariate analysis revealed that negative podoplanin expression in stromal fibroblasts was significantly associated with reduced disease-specific survival (p = 0.0017) and disease-free survival (p < 0.0001). Multivariate analysis revealed that negative podoplanin expression (p = 0.016) and lymph node metastasis (p = 0.027) were significantly associated with disease-free survival. CRC cell invasion was augmented by co-culture with CAFs that were treated with siRNA for podoplanin. Conclusions: Our results suggest that a positive podoplanin expression in stromal fibroblasts could have a protective role against CRC cell invasion and is a significant indicator of a good prognosis in patients with advanced CRC, supported by biological analysis showing that podoplanin expression in CAFs is associated with decreased CRC cell invasion.

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