title: Tumour necrosis factor-alpha and transforming growth factor-beta are significantly associated with better prognosis in non-small cell lung carcinoma: putative relation with BCL-2-mediated neovascularization.
abstract: Recent in vivo and in vitro studies have demonstrated a wide spectrum of biologic activities of cytokines in the pathogenesis and progression of malignancy. Tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) have emerged as two of the many host-derived mediators that seem to interfere with both antiproliferative and tumorigenic effects in malignant tumours including lung cancer. However, their association with tumour prognosis or prognostic factors has not yet been completely clarified. In this study, we assessed TNF-alpha and TGF-beta mRNA expression by RT-PCR technique in 61 NSCLC samples, demonstrating the presence of TNF-alpha and TGF-beta mRNA in 55.74% and 45.9% of cases, respectively. We also evaluated the expression of the two distinct transmembrane TNF receptors. TNFR-I and TNFR-II, with a PCR-positive signal in 70.49% and 65.57% of cases, respectively. In 49 of the 61 cases, we evaluated the prognostic impact of the two growth-inhibiting factors using the Kaplan-Meier analysis. In the univariate analysis patients without nodal metastatic involvement (P = 0.02), less advanced tumour stage (P = 0.02) or TNF-alpha and TGF-beta positive cancers (P = 0.01 and P = 0.03) showed a favourable prognosis in terms of overall survival. Since our previous studies demonstrated a significant association between NSCLC behaviour, neoangiogenesis and bcl-2 expression, we investigated the putative relation between TNF-alpha and TGF-beta on the one hand, and vascular count (as a measure of tumour angiogenesis) and bcl-2 protein expression, on the other hand. Our results showed a significant direct association between TNF-alpha and bcl-2 (P = 0.05) and an inverse association between TNF-alpha and microvessel count (P = 0.03). Moreover, as previously demonstrated, we observed a significant inverse correlation between bcl-2 protein expression and vascular count (P = 0.05), suggesting that the favourable effect of TNF-alpha on clinical outcome may be related to a bcl-2-mediated low neovascular development.
authors.affiliation: Department of Oncology, University of Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Boldrini
authors.forename: A
authors.initials: A
authors.lastname: Calcinai
authors.forename: E
authors.initials: E
authors.lastname: Samaritani
authors.forename: F
authors.initials: F
authors.lastname: Pistolesi
authors.forename: A
authors.initials: A
authors.lastname: Mussi
authors.forename: M
authors.initials: M
authors.lastname: Lucchi
authors.forename: C A
authors.initials: CA
authors.lastname: Angeletti
authors.forename: F
authors.initials: F
authors.lastname: Basolo
authors.forename: G
authors.initials: G
authors.lastname: Fontanini
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha