Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy.
Cancer-associated fibroblasts (CAFs) in the stroma play an important role in influencing the proliferation, invasion and metastasis of cancer cells. Fibroblast activation protein-α (FAP-α) is known as a marker of CAFs, while stromal cell-derived factor-1 (SDF-1) is primarily expressed by CAFs. Herein, we investigated whether the expression levels of these genes are associated with clinical outcome after pre-operative chemoradiotherapy (CRT) in rectal cancer patients. We obtained total RNA from residual cancer stroma using microdissection from a total of 52 rectal cancer specimens from patients who underwent pre-operative CRT, we performed transcriptional analyses, and the serum protein concentrations in 40 matched microdissected specimens were measured by enzyme-linked immunosorbent assay. Additionally, we sought to clarify the location of FAP-α and SDF-1 expression using immunohistochemical staining. Of the 52 patients, 15.6 and 36.8% showed detectable FAP-α and SDF-1 mRNA expression, respectively. A significant correlation was observed between stromal FAP-α and SDF-1 mRNA levels. Moreover, there was a significant correlation between stromal SDF-1 gene expression levels and serum protein levels. Patients who developed distant recurrences after CRT had positive expression of both genes (P<0.05). The positive expression of both genes was also associated with poor probability of recurrence-free and overall survival (P<0.05). Patients with elevated serum SDF-1 levels had equally poor overall survival as those with positive stromal SDF-1 gene expression (P<0.05). In immunohistochemistry, both FAP-α and SDF-1 expression was observed in certain activated fibroblasts. In conclusion, FAP-α and SDF-1 expression was shown to be involved in tumor re-growth and recurrence in rectal cancer patients treated with pre-operative CRT.
Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Mie, Japan. saigusa@clin.medic.mie-u.ac.jp
Susumu
S
Saigusa
Yuji
Y
Toiyama
Koji
K
Tanaka
Takeshi
T
Yokoe
Yoshinaga
Y
Okugawa
Hiroyuki
H
Fujikawa
Kohei
K
Matsusita
Mikio
M
Kawamura
Yasuhiro
Y
Inoue
Chikao
C
Miki
Masato
M
Kusunoki
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D054377:Chemokine CXCL12 / Q000032:analysis / Q000235:genetics; D003131:Combined Modality Therapy; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D018093:Gelatinases / Q000032:analysis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012004:Rectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
D014408:Biomarkers, Tumor; D054377:Chemokine CXCL12; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha