Claspin functions in cell homeostasis—A link to cancer?

Cancer remains one of the leading causes of mortality worldwide. Most cancers present high degrees of genomic instability. DNA damage and replication checkpoints function as barriers to halt cell cycle progression until damage is resolved, preventing the perpetuation of errors. Activation of these checkpoints is critically dependent on Claspin, an adaptor protein that mediates the phosphorylation of the effector kinase Chk1 by ATR. However, Claspin also performs other roles related to the protection and maintenance of cell and genome integrity. For instance, following DNA damage and checkpoint activation, Claspin bridges checkpoint responses to DNA repair or to apoptosis. During DNA replication, Claspin acts a sensor and couples DNA unwinding to strand polymerization, and may also indirectly regulate replication initiation at firing origins. As Claspin participates in several processes that are vital to maintenance of cell homeostasis, its function is tightly regulated at multiple levels. Nevertheless, little is known about its role in cancer. Accumulating evidence suggests that Claspin inactivation could be an essential event during carcinogenesis, indicating that Claspin may function as a tumour suppressor. In this review, we will examine the functions of Claspin and how its deregulation may contribute to cancer initiation and progression. To conclude, we will discuss means by which Claspin can be targeted for cancer therapy.     

Serum amyloid A and inflammasome activation: A link to breast cancer progression?

Breast cancer is the most frequently diagnosed cancer in women globally. Although there have been many significant advances made in the diagnosis and treatment of breast cancer, numerous unresolved challenges remain, which include prevention, early diagnosis, metastasis and recurrence. The role of inflammation in cancer development is well established and is believed to be one of the leading hallmarks of cancer progression. Recently, the role of the inflammasome, a cytosolic multiprotein complex, has received attention in different cancers. By contributing to the activation of inflammatory cytokines the inflammasome intensifies the inflammatory cascade. The inflammasome can be activated through several pathways, which include the binding of pattern associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to toll-like receptors (TLRs). Serum amyloid A (SAA), a non-specific acute-phase protein, can function as an endogenous DAMP by binding to pattern recognition receptors like TLRs on both breast cancer cells and cancer associated fibroblasts (CAFs). SAA can thus stimulate the production of IL-1β, thereby creating a favourable inflammatory environment to support tumour growth. The aim of this review is to highlight the possible role of SAA as an endogenous DAMP in the tumour microenvironment (TME) thereby promoting breast cancer growth through the activation of the NLRP3 inflammasome.     

An error catastrophe in cancer?

A comparison between the evolution of cancer cell populations and RNA viruses reveals a number of remarkable similarities. Both display high levels of plasticity and adaptability as a consequence of high degrees of genetic variation. It has been suggested that, as it occurs with RNA viruses, there is a threshold in the levels of genetic instability affordable by cancer cells in order to be able to overcome selection barriers (Trends Genet. 15 (1999) M57). Here we explore this concept by means of a simple mathematical model. It is shown that an error threshold exists in this model, which investigates both competition between cancer cell populations and its impact on overall tumor growth dynamics. Once the threshold is reached, the highly unstable tumor cell populations, which were sustaining malignant growth, become unable to maintain their genetic information, which in turn triggers a slowed down overall tumor growth regime.     

Does IFITM3 link inflammation to tumorigenesis?

Uncontrolled chronic inflammation, in most cases due to excessive cytokine signaling through their receptors, is known to contribute to the development of tumorigenesis. Recently, it has been reported that the antiviral membrane protein interferon-induced transmembrane protein 3 (IFITM3), induced by interferon signaling as part of the inflammatory response after viral infection, contributes to the development of B-cell malignancy. The unexpected oncogenic signaling of IFITM3 upon malignant B cell activation elucidated the mechanism by which the uncontrolled expression of inflammatory proteins contributes to leukemogenesis. In this review, the potential effects of inflammatory cytokines on upregulation of IFITM3 and its contribution to tumorigenesis are discussed.     

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.     

Dystonin/Bpag1--a link to what?

The dystonin/Bpag1 cytoskeletal interacting proteins play important roles in maintaining cytoarchitecture integrity in skin and in the neuromuscular system. The most profound phenotype observed in the dystonin mutant dystonia musculorum (dt) mice is a severe movement disorder, attributed in large part to sensory neuron degeneration. The molecular basis for this phenotype is currently not clear, despite several studies indicating possible causes for the pathology in dt mice. Complicating the picture of what essential dystonin functions are lost in dt mice is the fact that our understanding of the very nature of what dystonin is has evolved greatly over the past decade. Elucidating the roles of dystonin most relevant to neuronal function and survival should help to shed light on some of the common mechanisms underlying neurodegeneration.     

Tanning devices--fast track to skin cancer?

The use of UVB and/or UVA emitting devices for cosmetic tanning is widespread in Western populations including young people and is especially prevalent in females. Several epidemiological studies, although not all, have shown a significant relationship between the use of tanning devices and malignant melanoma after, in some cases, adjustment for confounding factors such as solar ultraviolet radiation (UVR) exposure. A relationship between solar exposure, especially intermittent exposure, and malignant melanoma is well established so it is not surprising that a similar connection has been reported for the use of tanning devices. Several epidemiological studies show that childhood exposure to sunlight is a risk factor for malignant melanoma and this may also be the case for the use of tanning devices, especially if sunburns are obtained. Some studies have evaluated the relationship between the use of tanning devices and non-melanoma skin cancer and at least one has suggested an association. The use of tanning devices by a substantial minority of young people is a worrying trend in terms of a likely increased incidence of malignant melanoma, and possibly non-melanoma cancers in the future. Although two recent reviews by epidemiologists conclude that a clear link between tanning devices and malignant melanoma is yet to be proven, there is a strong case for effective legislation to prohibit the use of tanning devices by people under 18 yr of age.