通常型膵癌進展におけるFibroblast activation protein α 発現に関する臨床病理学的検討

通常型膵癌(以下膵癌)は極めて予後不良な癌であり,病理学的には癌周囲に豊富な間質を伴う。固形癌の間質は癌の増殖,浸潤,転移や抗癌剤に対する抵抗性獲得に重要な役割を果たし,なかでも癌関連線維芽細胞(Carcinoma associated fibroblast:CAF)と呼ばれる癌間質の活性化線維芽細胞は癌進展に深く関与している.今回我々は膵癌組織のCAFに発現するFibroblast activation protein α(以下FAP)の臨床病理学的な意義について検討した.対象は2006年4月から2010年4月の間に当院で切除した膵癌症例30例である.抗FAP抗体を用いて免疫組織学的検討を行った.FAPは主として癌周囲の間質に検出され,一部には膵癌細胞にも認められたが,今回の検討ではFAP陽性の線維芽細胞をCAFとみなし,線維芽細胞のFAP発現強度と臨床病理学的因子を比較検討した.FAP陽性線維芽細胞は28/30例(93%)に認められた.FAP発現強度の内訳は,1+:8例,2+:16 例,3+:4例であった.陰性/弱陽性群(陰性・1+)と強陽性群(2+・3+)での生存率を比較したところ,それぞれの全生存日数の中央値は862日と352日であり強陽性群の生存率は有意に低かった(P<0.05).またFAPの発現強度と膵癌細胞の分化度は有意な関連性を示し,FAPの発現が強いほど有意に低分化であった.さらに多変量解析ではFAPの強陽性は膵癌患者の予後を規定する独立因子の一つであった.以上の成績から膵癌組織の線維芽細胞におけるFAPの発現は膵癌患者の予後を規定する重要なバイオマーカーであることが明らかとなり,膵癌細胞の分化度と相関することを初めて明らかにした.Pancreatic cancer is associated with an extremely poor prognosis, and pathologically shows abundant stroma surrounding cancer cells. The stroma of solid cancer plays an important role in cancer growth, invasion, metastasis, and the acquisition of resistance to anticancer drugs. In particular, activated fibroblasts in the cancer stroma called carcinomaassociated fibroblasts (CAFs) are closely involved in cancer progression. In this study, we evaluated the clinicopathological importance of fibroblast activation proteinα (FAP) that is expressed in CAFs in pancreatic cancer tissue. The subjects consisted of 30 patients with pancreatic cancer who underwent resection in our hospital between April 2006 and April 2010.Immunohistological evaluation was performed using the anti-FAP antibody.FAP was detected mainly in the stroma surrounding pancreatic cancer cells and partly in cancer cells. In this study, FAP-positive fibroblasts were regarded as CAFs, and the associations between the FAP expression level in fibroblasts and clinicopathological factors were evaluated. FAP-positive fibroblasts were observed in 28(93%) of the 30 patients. The FAP expression level was 1+ in 8 patients, 2+ in 16, and 3+ in 4. The survival rate was compared between the negative/weakly positive group (negative, 1+) and strongly positive group (2+, 3+). The medians of all survival periods were 862 and 352 days in the negative/weakly positive and strongly positive groups, respectively, and the survival rate was significantly lower in the latter (p<0.05). In addition, the FAP expression level was significantly correlated with the differentiation level of pancreatic cancer cells; when the FAP expression level was higher, differentiation was significantly poorer. Multivariate analysis revealed strongly FAP-positive fibroblasts to be an independent prognostic factor in patients with pancreatic cancer. These results show that FAP expression in fibroblasts in pancreatic cancer tissue is an important prognostic biomarker in patients with pancreatic cancer and correlated with the differentiation level of pancreatic cancer cells