Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Estimating the Burden of Malignant Neoplasm in Shandong Province [山东省恶性肿瘤疾病负担研究]

Objective To make a comprehensive estimation of the burden of malignant neoplasm in Shandong province by the means of disability- adjusted life year (DALY) for the first time. Methods DALYs were calculated following the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability. We measured YLLs using the cancer mortality data of 19 Disease Surveillance Points (DSPs) in Shandong Province during 2000 and 2005. YLDs were estimated based on the cancer morbidity data of 6 Cancer Incidence Surveillance Points in Shandong Province in 2005. Results All cancers were responsible for 20.60 DALYs for every thousand population in Shandong Province (25.30 for men and 15.74 for women) . 94.3% of the losses were due to premature death and 5.7% to disability. 31.9% of the DALYs happened among 45~59 age group. The top 10 cancers for DALYs were lung cancer, liver cancer, stomach cancer, oesophagus cancer, colon/rectum cancer, breast cancer, leukemia, brain cancer, pancreas cancer and cervix uteri cancer in turn. The burden of major cancers such as lung cancer and liver cancer in Shandong were heavier than the global and national level. Conclusions he burden of disease of malignant neoplasm is mainly because of premature death. Lung cancer, liver cancer, stomach cancer and oesophagus cancer are the major cancers in Shandong Province and should be paid more attention to their prevention and control. Abstract in Chinese 目的 首次应用伤残调整寿命年(DALY)对山东省居民恶性肿瘤疾病负担进行综合评价. 方法 以2000-2005年山东省疾病监测系统的恶性肿瘤死亡资料和2005年山东省恶性肿瘤发病监测系统的发病资料为基础,利用世界卫生组织提供的专门公式,计算恶性肿瘤的YLLs、YLDs和DALYs,以此评价恶性肿瘤的疾病负担. 结果 山东省每千人每年因恶性肿瘤造成20.60个DALYs损失(男性25.30,女性15.74),其中,9413%为早死所致,5.7%因残疾所致:恶性肿瘤主要导致45～59岁人群的DALYs损失,占31.93%;恶性肿瘤疾病负担前10位依次为肺癌、肝癌、胃癌、食道癌、肠癌、乳腺癌、白血病、脑癌、胰腺癌和宫颈癌;山东省肺癌、肝癌等主要癌症疾病负担高于全球和全国水平. 结论 恶性肿瘤疾病负担主要由早死所致,肺癌、肝癌、胃癌和食道癌等主要癌症的防制地位十分突出.

Estimating the burden of malignant neoplasm on village residents in a mountainous area [山区农村居民恶性肿瘤疾病负担的估计]

Objective To make a comprehensive estimation of the burden of malignant neoplasm on village residents in Linqu County by the means of DALY (Disability-adjusted life year). Methods DALYs, YLLs and YLDs were calculated following the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability, based on the cancer registration data of Linqu villages during 1998-2004, in order to measure the burden of various caners. Results All cancers were responsible for 20.00 DALYs for every thousand population in Linqu County (24.82 for men and 14.96 for women). 92.5% of the losses were due to premature death and 7.5% to disability. 31.5% of the DALYs happened among 45-59 age group. The top 10 cancers for DALYs were stomach cancer, lung cancer, liver cancer, oesophagus cancer, leukemia,colon/rectum cancer, brain cancer, pancreas cancer, breast cancer and bone cancer in turn. Only stomach cancer, lung cancer and liver cancer together account for 69.3% of total DALYs due to malignant neoplasm. The burden of malignant neoplasm was on rising recent years. Conclusions The burden of disease of malignant neoplasm is mainly because of premature death. Stomach cancer, lung cancer and liver cancer lead to heavier burden than the global and national levels. Abstract in Chinese 目的 应用伤残调整寿命年(DALY)对临朐县农村恶性肿瘤疾病负担进行评价. 方法 以1998～2004年临朐县农村肿瘤登记资料为基础,利用全球疾病负担研究中使用的专门公式计算恶性肿瘤的YLLs、YLDs和DALYs,以此评价各类恶性肿瘤的疾病负担. 结果 临朐农村每千人每年因恶性肿瘤造成20.0个DALYs损失(男性24.82,女性14.96),其中92.5%为早死所致,7.5%因残疾所致;恶性肿瘤主要导致45～59岁人群的DALYs损失,占31.5%;恶性肿瘤疾病负担前10位依次为胃癌、肺癌、肝癌、食道癌、白血病、肠癌、脑癌、胰腺癌、乳腺癌和骨癌,其中仅胃癌、肺癌和肝癌三大肿瘤DALYs就占全部肿瘤的69.3%;临朐县农村恶性肿瘤疾病负担有进一步上升的趋势. 结论 恶性肿瘤疾病负担主要由早死所致,胃癌、肺癌、肝癌等主要癌症疾病负担高于全球和中国区水平.

Economic burden of malignant neoplasms in Shandong province [山东省恶性肿瘤经济负担分析]

Objective: To evaluate the economic burden of malignant neoplasms in Shandong province in order to provide scientific evidence for policy-making. Methods: The main sources for this study were the data from the third sampling survey of death cause in 2006 and cancer prevalence survey in 2007 in Shandong province. The direct medical cost was calculated based on the survey data. The indirect cost due to mortality and morbidity were estimated with human capital approach based on the data of disability-adjusted life years derived from the two surveys and gross domestic product (GDP) data. The total economic burden was the sum of direct medical cost and indirect cost. The uncertainty analysis was conducted according to the methodology in global burden of disease study. Results: The total cost of cancer in Shandong province in 2006 estimated was 18 057 million Yuan RMB (95% confidence interval:16 817 － 19 393 million), which accounted for 0. 83% of the total GDP. The direct medical cost，indirect mortality cost and indirect morbidity cost accounted for 17.28%, 78.53%, and 4.20% of total economic burden of malignant neoplasms, respectively. Liver，lung and stomach cancer were the top three tumors with heavier economic burden, with accounted for more than one half (57. 83%) of the total economic burden of all cancers. The uncertainty of total burden estimated was around ± 7%, which mainly derived from the uncertainty of indirect economic burden. Conclusion: The influence of cancers on social economy is dominated by the loss of productivity, especially by the productivity loss due to premature death. Liver, lung and stomach cancer are the major cancers for disease control and prevention in Shandong province. Abstract in Chinese 目的 评价山东省恶性肿瘤经济负担,为卫生决策提供科学依据. 方法 以2006年山东省第3次死因回顾抽样凋查资料和2007年山东省恶性肿瘤现患状况抽样调查资料为基础,测算全省直接医疗成本;采用人力资本法测算死亡间接负担和伤残间接负担;参考全球疾病负担研究的方法对测算结果的不确定性进行分析. 结果 2006年山东省因恶性肿瘤导致的总经济负担为180.57亿元(95%CI=16 817～19 393),占全省GDP总量的0.83%,其中直接医疗成本占总负担的17.28%,死亡造成的间接经济负担占78.53%,伤残所致间接经济负担占4.20%;肝癌、肺癌和胃癌为山东省经济负担最重的3种恶性肿瘤,总经济负担合计占全部恶性肿瘤的57.83%;总经济负担估计结果的不确定性范围在±7%左右,主要取决于间接经济负担的不确定性. 结论 恶性肿瘤对社会经济的影响主要通过生产力的损失产生作用,并以死亡所致生产力损失为主;肝癌、肺癌和胃癌应是山东省恶性肿瘤预防控制的重点.

Estimation of disability weights on malignant neoplasms in Shandong province [山东省现患恶性肿瘤残疾权重的测量]

Objective To determine stage-specific and average disability weights (DWs) of malignant neoplasm and provide support and evidence for study on burden of cancer and policy development in Shandong province. Methods Health status of each cancer patient identified during the cancer prevalence survey in Shandong, 2007 was investigated. In line with the GBD methodology in estimating DWs, the disability extent of every case was classified and evaluated according to the Six-class Disability Classification version and then the stage-specific weights and average DWs with their 95 % confidence intervals were calculated, using SAS software. Results A total of 11 757 cancer cases were investigated and evaluated. DWs of specific stage of therapy, remission, metastasis and terminal of all cancers were 0.310, 0.218, 0.450 and 0.653 respectively. The average DW of all cancers was 0.317(95 % CI:0.312-0.321). Weights of different stage and different cancer varied significantly, while no significant differences were found between males and females. DWs were found higher (>0.4) for liver cancer, bone cancer, lymphoma and pancreas cancer. Lower DWs (<0.3) were found for breast cancer, cervix uteri, corpus uteri, ovarian cancer, larynx cancer, mouth and oropharynx cancer. Conclusion Stage-specific and average DWs for various cancers were estimated based on a large sample size survey. The average DWs of 0.317 for all cancers indicated that 1/3 healthy year lost for each survived life year of them. The difference of DWs between different cancer and stage provide scientific evidence for cancer prevention strategy development. Abstract in Chinese 目的 测算各种恶性肿瘤的分病程残疾权重和平均残疾权重,为山东省恶性肿瘤疾病负担研究及肿瘤防治对策制定提供参考依据. 方法 在山东省2007年恶性肿瘤现患调查中对所有恶性肿瘤患者的健康状况进行调查,参考全球疾病负担研究的方法 ,利用六级社会功能分级标准对患者残疾状况进行分级和赋值,分别计算20种恶性肿瘤的分病程残疾权重和平均残疾权重及其95%CI. 结果 共调查恶性肿瘤患者11757例,所有恶性肿瘤治疗期、恢复期、转移期和晚期的残疾权重分别为0.310、0.218、0.450和0.653,平均残疾权重为0.317(95%CI:0.312～0.321).不同恶性肿瘤和不同病程阶段的残疾权重差别显著,性别间差异无统计学意义.肝癌、骨癌、淋巴瘤和胰腺癌平均残疾权重较高(>0.4),乳腺癌、子宫体癌、子宫颈癌、卵巢癌、喉癌和口咽部癌症相对较低(<0.3). 结论 山东省恶性肿瘤平均残疾权重为0.317,即恶性肿瘤患者每存活1年平均损失近1/3个健康生命年;不同恶性肿瘤和不同病程阶段的残疾权重差别为肿瘤防治对策的制定具有重要意义.

Prognostic factors for malignant mesothelioma in 142 patients : validation of CALGB and EORTC prognostic scoring systems

Background The incidence of malignant mesothelioma is increasing. There is the perception that survival is worse in the UK than in other countries. However, it is important to compare survival in different series based on accurate prognostic data. The European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukaemia Group B (CALGB) have recently published prognostic scoring systems. We have assessed the prognostic variables, validated the EORTC and CALGB prognostic groups, and evaluated survival in a series of 142 patients. Methods Case notes of 142 consecutive patients presenting in Leicester since 1988 were reviewed. Univariate analysis of prognostic variables was performed using a Cox proportional hazards regression model. Statistically significant variables were analysed further in a forward, stepwise multivariate model. EORTC and CALGB prognostic groups were derived, Kaplan-Meier survival curves plotted, and survival rates were calculated from life tables. Results Significant poor prognostic factors in univariate analysis included male sex, older age, weight loss, chest pain, poor performance status, low haemoglobin, leukocytosis, thrombocytosis, and non-epithelial cell type (p<0.05). The prognostic significance of cell type, haemoglobin, white cell count, performance status, and sex were retained in the multivariate model. Overall median survival was 5.9 (range 0-34.3) months. One and two year survival rates were 21.3% (95% CI 13.9 to 28.7) and 3.5% (0 to 8.5), respectively. Median, one, and two year survival data within prognostic groups in Leicester were equivalent to the EORTC and CALGB series. Survival curves were successfully stratified by the prognostic groups. Conclusions This study validates the EORTC and CALGB prognostic scoring systems which should be used both in the assessment of survival data of series in different countries and in the stratification of patients into randomised clinical studies.

Angiogenesis is an independent prognostic factor in malignant mesothelioma

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at × 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease. © 2001 Cancer Research Campaign.

Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura

Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n = 35), inflamed pleura (IP, n = 12) and uninflammed pleura (UP, n = 14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan-Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P = 0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P = 0.03, total MMP-2 P = 0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM. © 2003 Cancer Research UK.

Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma

Objectives: Malignant mesothelioma (MM) is a fatal tumor of increasing incidence related to asbestos exposure. Microscopic tumor necrosis (TN) is a poor prognostic factor in solid tumors, but it has not been characterized in MM. We wished to evaluate the incidence of TN in MM and its correlations with clinicopathologic factors, angiogenesis, and survival. Methods: TN was graded in 171 routine formalin-fixed, paraffin-embedded hematoxylin-eosinstained tumor sections by two independent observers. Angiogenesis was assessed by the microvessel count (MVC) of CD34 immunostained sections. TN was correlated with survival by Kaplan-Meier and log-rank analysis, and stepwise, multivariate Cox models were used to compare TN with angiogenesis and established prognostic factors and prognostic scoring systems. Results: TN was identified in 39 cases (22.8%) and correlated with low hemoglobin (p = 0.01), thrombocytosis (p = 0.04), and high MVC (p = 0.02). TN was a poor prognostic factor in univariate analysis (p = 0.008). Patients with TN had a median survival of 5.3 months vs 8.3 months in negative cases. Independent indicators of poor prognosis in multivariate analysis were nonepithelioid cell type (p = 0.0001), performance status > 0 (p = 0.007), and increasing MVC (p = 0.004) but not TN. TN contributed independently to the European Organisation for Research and Treatment of Cancer (EORTC) [p = 0.03] and to the Cancer and Leukemia Group B (CALGB) [p = 0.03] prognostic groups in respective multivariate Cox analyses. Conclusions: TN correlates with angiogenesis and is a poor prognostic factor in MM. TN contributes to the EORTC and CALGB prognostic scoring systems.

EGFR expression : associations with outcome and clinicopathological variables in malignant pleural mesothelioma

Malignant mesothelioma (MM) is a fatal tumour of increasing incidence which is related to asbestos exposure. This work evaluated expression in MM of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry in 168 tumour sections and its correlations with clinicopathological and biological factors. The microvessel density (MVD) was derived from CD34 immunostained sections. Hematoxylin and eosin stained sections were examined for intratumoural necrosis. COX-2 protein expression was evaluated with semi-quantitative Western blotting of homogenised tumour supernatants (n = 45). EGFR expression was correlated with survival by Kaplan-Meier and log rank analysis. Univariate and multivariate Cox proportional hazards models were used to compare the effects of EGFR with clinicopathological and biological prognostic factors and prognostic scoring systems. EGFR expression was identified in 74 cases (44%) and correlated with epithelioid cell type (p < 0.0001), good performance status (p < 0.0001), the absence of chest pain (p < 0.0001) and the presence of TN (p = 0.004), but not MVD or COX-2. EGFR expression was a good prognostic factor in univariate analysis (p = 0.01). Independent indicators of poor prognosis in multivariate analysis were non-epithelioid cell type (p = 0.0001), weight loss, performance status and WBC > 8.3 × 10 9 L -1. EGFR status was not an independent prognostic factor. EGFR expression in MM correlates with epithelioid histology and TN. EGFR may be a target for selective therapies in MM. © 2006 Elsevier Ireland Ltd. All rights reserved.

Advances in the systemic therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.

Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma. © 2012 by the International Association for the Study of Lung.

Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent

Introduction: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM. Methods: The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. Results: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner. Conclusions: These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease. © 2011 Elsevier Ltd. All rights reserved.

Estimation of the burden of malignant neoplasms by DALYs in Shandong Province [应用伤残调整寿命年测量山东省恶性肿瘤疾病负担的研究]

Objective: To evaluate the burden of malignant neoplasms in Shandong Province in order to provide scientific evidence for policy-making. Methods: The main data for this study were from Shandong third cause of death sampling survey in 2006 and Shandong 2007 cancer prevalence survey. YLLs, YLDs, DALYs and disability weights of each type of cancers were calculated according to the global burdens of disease （GBD） methodology. The direct method was used to estimate YLDs. The uncertainty analysis was conducted following the methodology in GBD study. Results: The total cancers burden in Shandong population was 1 383 thousands DALYs. Lung cancer, liver cancer, stomach cancer and esophagus cancer were the top four cancers with the highest health burden. The burden of the four major cancers together accounted for 71.45% of the total burden of all cancers. 95% of the total burden of malignant tumors was caused by premature death, and only 5.26% of the total cancer burden was due to disability. The uncertainty of total burden estimate was around±11%， the uncertainty of YLDs was bigger than that of YLLs. Conclusion: The health burden due to cancers in Shandong population is heavier than that of the national average level. Liver cancer, lung cancer and stomach cancer should be the major cancers for disease control and prevention in Shandong.

The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease

Recent studies have demonstrated that angiogenesis and suppressed cell- mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein- Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-α, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-α have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease. (C) 2000 Elsevier Science Ltd.