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Original Research: Lung Cancer |

Podoplanin-Positive Cancer-Associated Fibroblasts Could Have Prognostic Value Independent of Cancer Cell Phenotype in Stage I Lung Squamous Cell CarcinomaPhenotype of Cancer Cells and Stromal Fibroblasts: Usefulness of Combining Analysis of Both Cancer Cell Phenotype and Cancer-Associated Fibroblast Phenotype

Shotaro Ono, MD; Genichiro Ishii, MD, PhD; Kanji Nagai, MD; Teruhisa Takuwa, MD; Junji Yoshida, MD; Mitsuyo Nishimura, MD; Tomoyuki Hishida, MD; Keiju Aokage, MD; Satoshi Fujii, MD; Norihiko Ikeda, MD; Atsushi Ochiai, MD, PhD
Author and Funding Information

From the Pathology Division, Research Center for Innovative Oncology (Drs Ono, Ishii, Takuwa, Fujii, and Ochiai), and the Division of Thoracic Surgery (Drs Ono, Nagai, Takuwa, Yoshida, Nishimura, Hishida, and Aokage), National Cancer Center Hospital East, Kashiwa, Chiba; and the Departments of Thoracic Surgery (Drs Ono and Ikeda), Tokyo Medical University, Shinjuku, Tokyo, Japan.

Correspondence to: Genichiro Ishii, MD, PhD, Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kahiwa, Chiba, Japan 277-0882; e-mail: gishii@east.ncc.go.jp


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: This work was supported by the Grant-in-Aid for Cancer Research [Grant 19-10] from the Ministry of Health, Labour, and Welfare, National Cancer Center Research and Development Fund, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control, the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO), and JSPS KAKENHI [Grants 20590417, 215981].


Chest. 2013;143(4):963-970. doi:10.1378/chest.12-0913
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Background:  The prognostic significance of the tumor microenvironment, which is created by both cancer cells and cancer-associated fibroblasts (CAFs), has been increasingly recognized. The purpose of this study was to analyze the prognostic markers of stage I squamous cell carcinoma (SqCC), with special reference to the immunophenotypes of both cancer cells and CAFs.

Methods:  A total of 142 patients with stage I SqCC were included in this study. We examined the expressions of E-cadherin, laminin-5, podoplanin, c-MET, carbonic anhydrase IX (CA-IX), CD10, and CD44 in the cancer cells and those of podoplanin, CA-IX, CD10, and CD44 in the CAFs to evaluate their prognostic value.

Results:  Patients with low E-cadherin expression in the cancer cells showed a significantly poorer prognosis than those with high E-cadherin expression in the cancer cells (P < .001). On the other hand, high podoplanin expression in the CAFs was also associated with a significantly poorer prognosis (P < .001). A multivariate analysis identified low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs as significantly independent prognostic factors for overall survival (P = .013 and P = .0011, respectively). According to subgroup analyses combining E-cadherin expression in cancer cells and podoplanin expression in CAFs, 5-year overall survival of patients with low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs was 7.0% and showed a significantly poorer prognosis as compared with other groups (P < .001).

Conclusions:  The current study indicates that immunophenotypes of CAFs could have a prognostic value independent of those of the cancer cells in SqCC.

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