Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma.
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.
Yamanashi
Takahiro
T
Pathology Division, National Cancer Center Research Institute and Hospital, Tokyo, Japan.
Nakanishi
Yukihiro
Y
Fujii
Gen
G
Akishima-Fukasawa
Yuri
Y
Moriya
Yoshihiro
Y
Kanai
Yae
Y
Watanabe
Masahiko
M
Hirohashi
Setsuo
S
D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007797:Laminin / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011509:Proteoglycans / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism*; D015996:Survival Rate; D000098853:Podoplanin
D014408:Biomarkers, Tumor; D003094:Collagen; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D007797:Laminin; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D034741:RNA, Small Interfering; C117468:PDPN protein, human; D000098853:Podoplanin; C059485:matrigel