Z Gastroenterol 2013; 51 - A79
DOI: 10.1055/s-0033-1347529

Myofibroblast-derived secreted frizzled-related protein 1 (SFRP1) can inhibit colorectal carcinoma field cancerization

G Valcz 1, V Patai 2, I Füri 2, A Kalmár 2, B Péterfia 2, F Sipos 2, T Krenács 3, N Nagy 3, G Barna 3, B Wichmann 1, B Molnár 2, Z Tulassay 1
  • 1Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
  • 22nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
  • 31st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

Background: Despite frequent mutations of canonical Wnt signal in colorectal cancer (CRC), the α-SMA+ myofibroblast-derived interellular Wnt regulator SFRP1 may play a crucial role in the inhibiton of autocrine Wnt loop in epithelial cells. This effect may appear in the genetically and epigenetically altered, but histologically normal adjacent tumor (NAT) areas and inhibit field cancerization.

Aims: We compared the SFRP1 protein expression and methylation patterns of SMA+ myofbroblasts in NAT and CRC areas. Our further aim was to demonstrate that the recombinant SFRP1 protein (as modell of myofbroblast origin) may act as a tumor supressor to cells which bearing Wnt signal mutation.

Materials and methods: We identified the SFRP1 expression of α-SMA positive cells by dual fluorescent immunohistochemistry in tissue specimens including both NAT and CRC regions as well (n = 5). α-SMA positive cells were laser capture microdissected from NAT (n = 3) and CRC (n = 3) samples and methylation status of SFRP1 was analyzed in these cells. Furthermore we examined the effect of recombinant SFRP1 protein to SW480 (APC mutant) and HCT-116 (β-catenin mutant) cell lines.

Results: We found significantly decreased percentage of α-SMA+/SFRP1+ stromal cells (27,65 ± 18,27) in CRC compared to NAT region (85,73 ± 12,61%; p > 0,001). In line with this, in CRC areas we found significantly increased SFRP1 DNA hypermethylation in laser capture microdissected α-SMA+ cells. We demonstrated apoptotic effect of exogenously administered SFRP1 protein in both SW480 and HCT-116 cell lines.

Conclusion: The myofibroblast-derived SFRP1 may act as a tumor supressor and inhibit field cancerization in NAT areas. Paralell with tumor growth the increased methylation of SFRP1 gene in stromal myofibroblast may cause a synergistic effect with the enhanced autocrine epithelial Wnt loop and APC mutation.