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PTCH1 +/- dermal fibroblasts isolated from healthy skin of Gorlin syndrome patients exhibit features of carcinoma associated fibroblasts.

Valin A, Barnay-Verdier S, Robert T, Ripoche H, Brellier F, Chevallier-Lagente O, Avril MF, Magnaldo T - PLoS ONE (2009)

Bottom Line: Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome.They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts.These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

View Article: PubMed Central - PubMed

Affiliation: CNRS FRE2939, Université Paris Sud-Institut Gustave Roussy, Villejuif, France.

ABSTRACT
Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

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NBCCS fibroblasts in organotypic cultures over-express TNC.Organotypic skin cultures with control keratinocytes and the indicated fibroblasts were developed and 5 µm paraffin sections were immunolabelled using anti-human TNC antibody. Note the barely detectable labelling of TNC in control dermis and its increase in both NBCCS fibroblast strains tested (6 and 10).
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pone-0004818-g003: NBCCS fibroblasts in organotypic cultures over-express TNC.Organotypic skin cultures with control keratinocytes and the indicated fibroblasts were developed and 5 µm paraffin sections were immunolabelled using anti-human TNC antibody. Note the barely detectable labelling of TNC in control dermis and its increase in both NBCCS fibroblast strains tested (6 and 10).

Mentions: The mRNAs of some of the components of the extracellular matrix (ECM) were also found up-regulated in the missense and the nonsense NBCCS pools. For instance, the amount of collagen type 11 alpha 1 (COL11A1) mRNA was increased by 9.8 and 5.5 and tenascin C (TNC) mRNA was increased by 1.4 and 1.3 in the missense and the nonsense pools, respectively (Table 1 and Table S1). RT-QPCR confirmed the increased level of COL11A1 mRNA in 5 of the 6 NBCCS fibroblasts compared to control fibroblasts. The average rate of COL11A1 mRNA over-expression in NBCCS fibroblasts was 11.47 (Table 2). The slight increased level of TNC mRNA was confirmed by RT-QPCR (1.22 fold; Table 2) and immunohistochemistry performed on organotypic skin cultures comprising fibroblasts isolated from two independent NBCSS patients studied here revealed a stronger TNC over-expression (Figure 3).


PTCH1 +/- dermal fibroblasts isolated from healthy skin of Gorlin syndrome patients exhibit features of carcinoma associated fibroblasts.

Valin A, Barnay-Verdier S, Robert T, Ripoche H, Brellier F, Chevallier-Lagente O, Avril MF, Magnaldo T - PLoS ONE (2009)

NBCCS fibroblasts in organotypic cultures over-express TNC.Organotypic skin cultures with control keratinocytes and the indicated fibroblasts were developed and 5 µm paraffin sections were immunolabelled using anti-human TNC antibody. Note the barely detectable labelling of TNC in control dermis and its increase in both NBCCS fibroblast strains tested (6 and 10).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654107&req=5

pone-0004818-g003: NBCCS fibroblasts in organotypic cultures over-express TNC.Organotypic skin cultures with control keratinocytes and the indicated fibroblasts were developed and 5 µm paraffin sections were immunolabelled using anti-human TNC antibody. Note the barely detectable labelling of TNC in control dermis and its increase in both NBCCS fibroblast strains tested (6 and 10).
Mentions: The mRNAs of some of the components of the extracellular matrix (ECM) were also found up-regulated in the missense and the nonsense NBCCS pools. For instance, the amount of collagen type 11 alpha 1 (COL11A1) mRNA was increased by 9.8 and 5.5 and tenascin C (TNC) mRNA was increased by 1.4 and 1.3 in the missense and the nonsense pools, respectively (Table 1 and Table S1). RT-QPCR confirmed the increased level of COL11A1 mRNA in 5 of the 6 NBCCS fibroblasts compared to control fibroblasts. The average rate of COL11A1 mRNA over-expression in NBCCS fibroblasts was 11.47 (Table 2). The slight increased level of TNC mRNA was confirmed by RT-QPCR (1.22 fold; Table 2) and immunohistochemistry performed on organotypic skin cultures comprising fibroblasts isolated from two independent NBCSS patients studied here revealed a stronger TNC over-expression (Figure 3).

Bottom Line: Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome.They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts.These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

View Article: PubMed Central - PubMed

Affiliation: CNRS FRE2939, Université Paris Sud-Institut Gustave Roussy, Villejuif, France.

ABSTRACT
Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

Show MeSH
Related in: MedlinePlus