Tumour necrosis factor-alpha expression in tumour islets confers a survival advantage in non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>The role of TNFα in cancer is complex with both pro-tumourigenic and anti-tumourigenic roles proposed. We hypothesised that anatomical microlocalisation is critical for its function.</p> <p>Methods</p> <p>This study used immunohistochemistry to investigate the expression of TNFα in the tumour islets and stroma with respect to survival in 133 patients with surgically resected NSCLC.</p> <p>Results</p> <p>TNFα expression was increased in the tumour islets of patients with above median survival (AMS) compared to those with below median survival (BMS)(p = 0.006), but similar in the stroma of both groups. Increasing tumour islet TNFα density was a favorable independent prognostic indicator (p = 0.048) while stromal TNFα density was an independent predictor of reduced survival (p = 0.007). Patients with high TNFα expression (upper tertile) had a significantly higher 5-year survival compared to patients in the lower tertile (43% versus 22%, p = 0.01). In patients with AMS, 100% of TNFα⁺cells were macrophages and mast cells, compared to only 28% in the islets and 50% in the stroma of BMS patients (p < 0.001).</p> <p>Conclusions</p> <p>The expression of TNFα in the tumour islets of patients with NSCLC is associated with improved survival suggesting a role in the host anti-tumour immunological response. The expression of TNFα by macrophages and mast cells is critical for this relationship.</p

Chronic immune activation and inflammation as the cause of malignancy

Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. © 2001 Cancer Research Campaign http://www.bjcancer.co

Angiogenesis as a biomarker and target in cancer chemoprevention.

Angiogenesis, the formation of new blood vessels from existing vasculature, is essential to the late stages of carcinogenesis, allowing tumours to grow beyond 1-2 mm in diameter, invade surrounding tissue, and metastasise. However, more than two decades ago, angiogenesis that preceded neoplastic transformation was seen. Indeed, it can be detected in inflammatory and infectious diseases that increase the risk of developing cancer. Recent advances in fluorescence endoscopy and histological assessment suggest that, for certain cancers, the degree of new blood-vessel formation may differ between the early and late stages of carcinogenic progression. The association between angiogenesis and cancer occurrence, and ease of detection of this process in accessible tissues early in carcinogenesis, mean that angiogenesis fulfils the criteria for a biomarker of the effectiveness of chemopreventive intervention. There is also some evidence that biochemical assays of angiogenic growth factors may offer similar potential as surrogate biomarkers. Many natural and synthetic chemopreventive agents in development or in clinical use inhibit new vessel formation in vivo. Validation of angiogenesis as a biomarker for the effectiveness of chemoprevention should further the advancement of some chemopreventive agents