Stromal VCAN expression as a potential prognostic biomarker for disease recurrence in stage II-III colon cancer.
To develop prognostic biomarkers that can discriminate stage II-III colorectal cancer patients with high risk of postoperative recurrence, we conducted a genome-wide screening of relapse-related genes utilizing multiple microarray cohorts. Among differentially expressed genes between tumor and nontumor, we identified eight candidate genes associated with relapse in two datasets of stage II-III patients (n = 94 and 145, respectively, P < 0.05). Using datasets of laser-microdissected samples and FACS-purified cell populations, the localization of candidate genes, including COL4A2, COL4A1, VCAN and SERPINE1, were found predominantly in cancer stroma rather than epithelial components. Among those relapse-related stromal genes, VCAN mRNA, specifically expressed in cancer-associated fibroblasts, was further validated to be a prognostic factor in two additional independent datasets, consisting of 453 (P = 0.0334) and 89 (P = 0.0041) stage II-III patients. Furthermore, in our large set of formalin-fixed paraffin-embedded cohort (n = 338), VCAN protein was detected exclusively in cancer stroma by immunohistochemistry, demonstrating a stepwise increase of stromal VCAN from normal tissues through stage 0 to stage IV tumors. Stromal VCAN protein was associated with shorter relapse-free survival (RFS) in stage II-III colon cancer, independent of other clinical factors by multivariate analysis (P = 0.004). Stratified analyses revealed that stromal VCAN was a strong prognostic indicator particularly in stage II colon cancer (P = 0.0029). In all five analyzed cohorts, the expression of VCAN, in transcript or protein levels, was associated with poor RFS in stage II-III patients. We conclude that VCAN is a promising biomarker to identify stage II-III patients at high risk of relapse who may benefit from intensive postoperative management.
Department of Organ Regulatory Surgery , and.
Shun
S
Chida
Department of Organ Regulatory Surgery , and.
Hirokazu
H
Okayama
Department of Organ Regulatory Surgery , and.
Masaru
M
Noda
Department of Organ Regulatory Surgery , and.
Katsuharu
K
Saito
Department of Organ Regulatory Surgery , and.
Takahiro
T
Nakajima
Department of Organ Regulatory Surgery , and.
Keita
K
Aoto
Department of Organ Regulatory Surgery , and.
Suguru
S
Hayase
Department of Organ Regulatory Surgery , and.
Tomoyuki
T
Momma
Department of Organ Regulatory Surgery , and.
Shinji
S
Ohki
Department of Organ Regulatory Surgery, and.|Department of Advanced Cancer Immunotherapy, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima city, Fukushima, 960-1295, Japan.
Koji
K
Kono
Department of Organ Regulatory Surgery , and.
Seiichi
S
Takenoshita
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D003110:Colonic Neoplasms / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis*; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D017154:Stromal Cells / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053675:Versicans / Q000032:analysis* / Q000235:genetics
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C508322:VCAN protein, human; D053675:Versicans