Passive smoking and lung cancer: a publication bias?

To assess the likelihood of publication bias in a recent review of the effect of passive smoking on lung cancer the evidence from the reviewed papers was visualised on a “funnel” plot. In such a plot if the relative risks from various studies are plotted according to sample size they should scatter round some underlying true value, the scatter being greatest where the studies have the lowest statistical power—thus showing a “funnel” pattern. If there is publication bias and studies with non-significant results are not being published there should be a “gap” in the plot. The logarithm of the relative risks was plotted against the standard error of the logarithm of the relative risk (which was used instead of sample size as a measure of statistical uncertainty). The resulting plot was compatible with a publication bias but only in studies on men.Further studies of passive smoking and lung cancer in men seem to be warranted.     

Ovarian cancer and ovulation induction drugs--is there a link?

Screening for ovarian cancer in a group of women with induced ovulations was encouraged by recently reported controversies about a possible association between the use of ovulation induction drugs and the increased risk of ovarian carcinoma. Transvaginal color Doppler ultrasonography was applied in screening for early stage ovarian malignoma in 110 asymptomatic women who received an ovulation induction therapy for infertility. Already reported standard parameters for discriminating malignant from benign flows, such as resistance index RI < 0.40, pulsatility index PI < 1 and morphological score (borders, cyst quality, septate areas, papilla and ovarian tissue echogenicity) were used. Screening included 110 women and was carried out from April 1, 1198 to March 31, 1999. Seven examinees had abnormal ovarian findings. The finding spontaneously regressed in five of them, one underwent surgery for a persistent cyst with a benign pathohistologic diagnosis, and one was diagnosed with early stage ovarian malignoma. RI < 0.40 was reported in one patient (0.9%) with a morphologically suspect finding and a pathohistologically confirmed malignoma, PI < 1 was found in 40 subjects or 36.4%, while malignoma was demonstrated in one case alone. The results showed the advantage of RI over PI in discriminating malignant from benign structures. The association between the use of ovulation stimulation drugs and the increased risk of ovarian carcinoma remains unproved and also challenges new dilemmas. The paper cautions against undesirable, potentially serious long-term effects of the use of ovulation induction agents. Additional trials should therefore be performed including a long-term prospective follow-up of women with induced ovulations.     

Viruses and oral cancer. Is there a link?

Oral squamous cell carcinoma (OSCC) is the most common malignant tumour of the oral cavity. The aetiology of epithelial cancer of the head and neck is considered to be a multifactorial, sequential process. DNA viruses are found in many different cancers and are also capable of transforming cells to a malignant phenotype. Human Papilloma Virus (HPV) has been proposed as risk factors in OSCC development and HPV type 16 is the most important subtype. Other oncogenic virus species i.e., Epstein–Barr Virus and Herpes Simplex Virus Type 1 have been proposed to be involved in oral carcinogenesis. However, no convincing evidence exist that they are an established risk factor in OSCC. Therefore more studies are needed in order to clarify the different aspects of virus involvement. Here, we review the existing literature on viral involvement in oral cancer.     

Schizophrenia and cancer: Is angiogenesis a missed link?

Cancer prevalence and risk in schizophrenia (SZ) patients, as well as their implicated molecular pathways, is a debate that has become increasingly appreciated, despite lacking evidence. Since angiogenesis is imbalanced in both conditions, a non-systematic review of the existing literature using the PubMed database was performed to summarize current knowledge and to elucidate hypothesis regarding the reduced incidence of cancer in SZ, exploring possible angiogenesis biology aspects that can be interrelated both with SZ and cancer. Some lines of evidence based in epidemiology, genetic, molecular and biochemical studies suggest a putative interplay between SZ pathophysiology and angiogenesis, involving different molecular pathways and also influencing cancer biology. Studying angiogenesis in SZ and its implications to cancer is an unexplored field that could provide more insightful knowledge regarding its pathophysiology and promote the development of treatment applications.     

Aurora kinases, aneuploidy and cancer, a coincidence or a real link?

As Aurora kinases are overexpressed in a large number of cancers, and ectopic expression of Aurora generates polyploid cells containing multiple centrosomes, it has been tempting to suggest that Aurora overexpression provokes genetic instability underlying the tumorigenesis. However, examination of the evidence suggests a more complex relationship. Overexpression of Aurora-A readily transforms rat-1 and NIH3T3 cells, but not primary cells, whereas overexpression of Aurora-B induces metastasis after implantation of tumors in nude mice. Why do polyploid cells containing abnormal centrosome numbers induced by Aurora not get eliminated at cell-cycle checkpoints? Does this phenotype determine the origin of cancer or does it only promote tumor progression? Would drugs against Aurora family members be of any help for cancer treatment? These and related questions are addressed in this review (which is part of the Chromosome Segregation and Aneuploidy series).     

Keratin 20 - a diagnostic and prognostic marker in colorectal cancer?

Colorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (≥50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients' outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing.     

Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis

Tumor necrosis factor alpha (TNF-α) is a vital cytokine involved in inflammation, immunity, and cellular organization. The TNFA-308G/A (rs1800629) and -238G/A (rs361525) polymorphisms are two widely investigated variants for their associations with risk of cervical cancer, but the results are conflicting. Here, we performed a meta-analysis to pool the data and evaluate the between-studies heterogeneity. All the case–control studies published from January 1989 to October 2010 on the association between the two polymorphisms of TNFA and cervical cancer risk were identified by searching the electronic literature Medline. The cervical cancer risk associated with the two polymorphisms of TNFA gene was estimated for each study by OR together with its 95% CI, respectively, by using the Review Manager 4.2 software. It was showed that the variant homozygote -308AA was associated with a significantly increased risk of cervical cancer (AA vs. GG: OR = 1.41, 95% CI = 1.03–1.92, P = 0.033; AA vs. GA/GG: OR = 1.39, 95% CI = 1.02–1.90, P = 0.036), and the effect was more evident among Asians (AA vs. GA/GG: OR = 3.67, 95% CI = 1.25–10.81, P = 0.018). We also found that the variant genotypes -238GA/AA was associated with a significantly decreased risk of cervical cancer (GA/AA vs. GG: OR = 0.55, 95% CI = 0.41–0.74, P < 0.001). The results suggested that TNFA-308G/A and -238G/A may contribute to cervical cancer susceptibility.     

Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant?

Cisplatin-induced apoptosis in epithelial ovarian cancer cells is in part a consequence of suppressed Xiap expression and upregulation of the Fas/FasL system. Changes in the expression of these 'cell death' and 'cell survival' genes lead to activation of caspase-3, and cleavage of MDM2 and FAK. Failure of cancer cells to maintain a balance in the expression of these genes in favor of apoptotic cell death may be an important factor of chemoresistance. Xiap may be a novel target for gene therapy of human ovarian epithelial cancer and, dependent on P53 status, expression of Xiap antisense alone or in combination with wild-type P53 sense may offer a new approach for the treatment of the chemoresistant cancer.     

Why cancer and inflammation?

Central to the development of cancer are genetic changes that endow these “cancer cells” with many of the hallmarks of cancer, such as self-sufficient growth and resistance to anti-growth and pro-death signals. However, while the genetic changes that occur within cancer cells themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and progression are dependent on ancillary processes provided by cells of the tumor environment but that are not necessarily cancerous themselves. Inflammation has long been associated with the development of cancer. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer.     

Exosomes at a glance – common nominators for cancer hallmarks and novel diagnosis tools

Cancer represents a heterogeneous disease with multiple levels of regulation and a dynamic environment that sustains the evolution of the malignant mass. This dynamic is in part sustained by a class of extracellular vesicles termed exosomes that are able to imprint the pathological state by incorporating differential cargos in order to facilitate cell-to-cell communication. Exosomes are stable within the extracellular medium and function as shuttles secreted by healthy or pathological cells, being further taken by the accepting cell with direct effects on its phenotype. The exosomal trafficking is deeply involved in multiple levels of cancer development with roles in all cancer hallmarks. Nowadays, studies are constantly exploring the ability of exosomes to sustain the malignant progression in order to attack this pathological trafficking and impair the ability of the tumor mass to expand within the organisms. As important, the circulatory characteristics of exosomes represent a steady advantage regarding the possibility of using them as minimally invasive diagnosis tools, where cancer patients’ present modified exosomal profiles compared to the healthy ones. This last characteristic, as novel diagnosis tools, has the advantage of a possible rapid transition within the clinic, compared to the studies that evaluate the therapeutic meaning.     

The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.