Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association

Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC.     

Carcinogenesis of Pancreatic Adenocarcinoma: Precursor Lesions

Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.     

Molecular Research in Penile Cancer—Lessons Learned from the Past and Bright Horizons of the Future?

Penile cancer is a rare tumor. There is a limited understanding of the biological mediators of prognostic and therapeutic importance in penile cancer. However, there exists some fundamental understanding of the major pathways involved in the development of penile pre-neoplastic lesions and neoplasms. The aim of the present review is to highlight our current state of molecular knowledge in penile cancer to foster the necessary tools for researchers to pave major advancements in our current treatment paradigms and cancer specific outcomes.     

“从生物学观点探讨辐射防护政策的新思路”研讨会简介

介绍了 2 0 0 0年 5月 1 7日在日本广岛举行的“从生物学观点探讨辐射防护政策的新思路”研讨会上 ,由 D.Preston,Y.Ishikawa,P.Duport,C.Streffer,M.Ohtaki,M.N.Mohankumar和 X.A.Chen等 7位专家所作的发言 ,内容包括 :广岛和长崎原子弹爆炸幸存者的辐射效应 ;二氧化钍造影剂病人肝和肺的致癌 ;受到低剂量电离辐射照射的动物的癌的危险 ;辐射诱发癌的致癌机制 ;把诱发遗传不稳定性假说作为依据的辐射致癌的数学含义 ;对电离辐射的适应性响应及其在影响放射防护标准中的作用以及长期吸入钍尘对健康影响的 1 4年追踪。     

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)–receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.     

Cervical Carcinoma: Oncobiology and Biomarkers

Cervical cancer is one of the most common types of carcinomas causing morbidity and mortality in women in all countries of the world. At the moment, the oncology, oncobiology, and oncomorphology of cervical cancer are characterized by the accumulation of new information; various molecular biological, genetic, and immunohistochemical methods of investigation of the mechanisms of cervical carcinogenesis are tested and applied; targeted antitumour drugs and diagnostic, prognostic, and predictive biomarkers are being searched for. Many issues of the etiopathogenesis of cervical cancer have not been sufficiently studied, and the role of many biomarkers characterizing various stages of cervical carcinogenesis remains unclear. Therefore, the target of this review is to systematize and understand several problems in the pathogenesis of cervical cancer and to evaluate the significance and role of biomarkers in cervical carcinogenesis.     

Molecular Mechanisms of Malignant Transformation of Oral Submucous Fibrosis by Different Betel Quid Constituents—Does Fibroblast Senescence Play a Role?

Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids—arecoline, arecaidine, guvacoline and guvacine—together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users.     

非诱变偶氮染料的研究进展(I)──偶氮染料诱变性研究方法及其致癌机理

主要讨论了偶氮染料诱变性能研究方法及其致癌机理。偶氮染料诱变性能研究方法多采用“Ａｍｅｓ／Ｓａｌｍｏｎｅｌｌａ”测试法,而其致癌机理,目前大多数专家认为主要是通过它在动物（或人）体内偶氮还原开裂形成的芳胺或其相关化合物特别是芳氮烯阳离子来实现的。     

Genotoxicity of estrogens

 Genotoxic effect of the endogenous mammalian estrogen 17β-estradiol and the synthetic estrogen diethylstilbestrol have recently been demonstrated, e. g. the induction of numerical chromosome aberrations (aneuploidy, i. e., the condition in which one or more whole chromosomes of a normal set are missing or present in more than the usual set of copies) and the formation of deoxyribonucleic acid (DNA) adducts. It is likely that the genotoxicity of the estrogens acts in concert with their hormonal activity to give rise to their carcinogenic effects. Many of the phytoestrogens that occur in plants and the numerous anthropogenic estrogens in our environment, which are ingested with food, have not yet been examined for their genotoxic potential. Recent studies have demonstrated that some but not all of these estrogens exhibit genotoxicity. The type and strength of the genotoxicity strongly depends on the chemical structure and does not correlate with estrogenicity. For example, coumestrol and genistein are clastogenic in cultured mammalian cells and lead to gene mutations, whereas biochanin-A and bisphenol-A have the potential to cause aneuploidy. Daidzein, enterolactone, enterodiol and certain bisphenols are devoid of genotoxic effects. The genotoxicity should be determined individually for each estrogen and taken into account in the assessment of its carcinogenic risk. Received: 19 December 1997