Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy
Cancer Microenvironment - 2013
Tóm tắt
Cancer-associated fibroblasts (CAFs) play an important role in tumor initiation and progression. The aim of this study is to explore the role of 2 CAF markers, fibroblast activated protein (FAP) and α-smooth muscle actin (αSMA), in patients with epithelial ovarian cancer (EOC) post-neoadjuvant chemotherapy. Sixty-six patients with the diagnosis of EOC treated with debulking surgery after neoadjuvant therapy were retrieved from the archives. Immunohistochemistry for FAP and αSMA antibodies were performed on paraffin-embedded tissue. Fisher’s exact test was performed to test the association between FAP and αSMA expression and disease status. Kaplan–Meier method with log-rank test was used to check the survival difference between different FAP tumor/stroma expressions. FAP stroma
pos
. expression was strongly associated with higher recurrences rate [OR: 15.95; 95 % CI: 1.521–835.206; p = 0.0072]. Cases with combined FAP stroma
pos
and FAP tumor
neg
had higher death rate [OR: 4.845; 95 % CI: 1.53–16.61; p = 0.0046] and higher recurrence rate [OR: 5.12; 95 % CI: 0.91–54.42; p = 0.0487] compared to all the others. Cases with combined FAP stroma
neg
and FAP tumor
neg
were more likely to have lower recurrence rates [OR: 0.086; 95 % CI: 0.001–0.997; p = 0.0248]. αSMA was expressed by tumor-associated stroma in 95 % of cases and by tumor cells in 9 % of cases. No statistical power was found for αSMA and disease status. Our data indicate that FAP plays an important role in predicting tumor aggressiveness in patients with EOC post-neoadjuvant therapy, and its frequent expression in this malignancy implicates that FAP targeted therapy could be a very attractive strategy.
Từ khóa
Tài liệu tham khảo
The National Cancer Institute’s Surveillance, Epidemiology and End Results Program. The Center for Disease Control and Prevention’s National Program of Cancer Registries 2012. SEER.cancer.gov
du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M et al (2005) 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference. Ann Oncol 16(Suppl 8):viii7–viii12
Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N et al (2010) Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943–953
McCluggage WG, Lyness RW, Atkinson RJ, Dobbs SP, Harley I, McClelland HR et al (2002) Morphological effects of chemotherapy on ovarian carcinoma. J Clin Pathol 55:27–31
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petoit JF et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73:2680–2686
Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401
Franco OE, Shaw AK, Strand DW, Hayward SW (2012) Cancer associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol 21:33–39
Otsman A, Augesten M (2009) Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev 19:67–73
Lai D, Ma L, Wang F (2012) Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol 41:541–550
Brennen WN, Rosen DM, Wang H, Isaacs JT, Denmeade SR (2012) Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst 104:1320–1334
Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA (2009) Cancer fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS ONE 4:e7965
De Wever O, Demetter P, Mareel M, Bracke M (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238
Garin-Chesa P, Old LJ, Rettig WJ (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A 87:7235–7239
Scalan MJ, Raj BKM, Calvo B, Garin-Chelsa P, Sanz-Moncasi MP, Healey JH et al (1994) Molecular cloning of fibroblast activation protein α, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A 91:5657–5661
Mueller MM, Fusenig NE (2004) Friends or foes-bipolar effects of the tumor stroma in cancer. Nat Rev Cancer 4:839–849
Servais C, Erez N (2013) From sentinel cells to inflammatory culprits: cancer-associated fibroblasts in tumour-related inflammation. J Pathol 229:198–207
Anderberg C, Pietras K (2009) On the origin of cancer-associated fibroblasts. Cell Cycle 10:1461–1465
Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug update. J Clin Invest 116:1955–1962
O’Brien P, O’Connor BF (2008) Seprase: an overview of an important matrix serine protease. Biochim Biophys Acta 1784:1130–1145
Yu DM, Yao TW, Chowdhury S, Nadvi NA, Osborne B, Church WB et al (2010) The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J 277:1126–1144
Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B et al (2009) Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 4:e4992
Ge Y, Zhan F, Barlogie B, Epstein J, Shaughnessy J Jr, Yaccoby S (2006) Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. Br J Haematol 133:83–92
Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z et al (2008) Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas 37:154–158
Shi M, Yu DH, Chen Y, Zhao CY, Zhang J, Liu QH et al (2012) Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance. World J Gastroenterol 18:840–846
Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA et al (2007) Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 13:1736–1741
Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D et al (2011) Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett 303:47–55
Radisky DC, Kenny PA, Bissell MJ (2007) Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101:830–839
Monsky WL, Lin CY, Aoyama A, Kelly T, Akiyama SK, Mueller SC et al (1994) A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells. Cancer Res 54:5702–5710
Ariga N, Sato E, Ohuchi N, Nagura H, Ohtani H (2001) Stromal expression of fibroblast activation protein/seprase, a cell membrane serine proteinase and gelatinase, is associated with longer survival in patients with invasive ductal carcinoma of breast. Int J Cancer 95:67–72
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504
Brennen WN, Isaacs JT, Denmeade SR (2012) Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 11:257–266