Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype.
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 5 .013 and P 5 .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.
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba; Departments of Thoracic Surgery, Tokyo Medical University, Shinjuku, Tokyo, Japan.
Shotaro
S
Ono
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba. Electronic address: gishii@east.ncc.go.jp.
Genichiro
G
Ishii
Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Kanji
K
Nagai
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Teruhisa
T
Takuwa
Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Junji
J
Yoshida
Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Mitsuyo
M
Nishimura
Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Tomoyuki
T
Hishida
Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba.
Keiju
K
Aokage
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba.
Satoshi
S
Fujii
Departments of Thoracic Surgery, Tokyo Medical University, Shinjuku, Tokyo, Japan.
Norihiko
N
Ikeda
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba.
Atsushi
A
Ochiai
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D005500:Follow-Up Studies; D006801:Humans; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D015260:Neprilysin / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D015996:Survival Rate; D000098853:Podoplanin
D014408:Biomarkers, Tumor; D015820:Cadherins; D008562:Membrane Glycoproteins; D015260:Neprilysin; C117468:PDPN protein, human; D000098853:Podoplanin