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BBA - Reviews on Cancer (v.1795, #2)
Oxidative stress-related aging: A role for prostate cancer? by Alba Minelli ⁎; Ilaria Bellezza; Carmela Conte; Zoran Culig (pp. 83-91).
Prostate cancer has the highest prevalence of any non-cutaneous cancer in the human body and essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. Aging, considered as an impairment of body functions over time, caused by the accumulation of molecular damage in DNA, proteins and lipids, is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging. The aging damage may eventually appear in age-related health issues, which have a significant impact on the independence, general well-being and morbidity of the elderly. The association of aging with prostate cancer is undisputable as well as the association of aging with oxidative stress. Nevertheless, supportive evidence linking an increase in oxidative stress with prostate cancer is still scarce. This review is a comprehensive, literature-based analysis of the association of human prostate cancer with oxidative stress. The objective was to examine the involvement of reactive oxygen species in the mechanisms of prostatic carcinogenesis since the understanding of risk factors for prostate cancer has practical importance for public health, genetic and nutritional education, and chemoprevention.
Keywords: p53; Sexual hormone; Growth factor; Microenvironment; Vitamin D; Changes in oxidative defence system; Inflammation
Human cancer cell lines: Experimental models for cancer cells in situ? For cancer stem cells? by W.C.G. van Staveren; D.Y. Weiss Solís; A. Hébrant; V. Detours; J.E. Dumont; C. Maenhaut (pp. 92-103).
Established human cancer cell lines are routinely used as experimental models for human cancers. Their validity for such use is analyzed and discussed, with particular focus on thyroid tumors. Although cell lines retain some properties of the cells of origin, from the points of view of their genetics, epigenetics and gene expression, they show clear differences in these properties compared to in vivo tumors. This can be explained by a prior selection of initiating cells and a Darwinian evolution in vitro. The properties of the cell lines are compared to those of the postulated cancer stem cells and their use as models in this regard are discussed. Furthermore, other proper and possible uses of the cell lines are discussed.
Keywords: Human cancer cell line; Pitfall; Opportunities; Evolution; Oncogene addiction; Cancer stem cell
The dynamic and static modification of the epigenome by hormones: A role in the developmental origin of hormone related cancers by Karen Chiam; Wayne D. Tilley; Lisa M. Butler; Tina Bianco-Miotto ⁎ (pp. 104-109).
There are numerous diseases associated with abnormal hormonal regulation and these include cancers of the breast and prostate. There is substantial evidence that early hormonal perturbations (in utero or during early development) are associated with increased disease susceptibility later in life. These perturbations may arise from exposure to environmental agents or endocrine disruptors which mimic hormones and disrupt normal hormonal signaling. Epigenetic alterations have often been proposed as the underlying mechanism by which early hormonal perturbations may give rise to disease in adulthood. Currently, there is minimal evidence to support a direct link between early hormonal perturbations and epigenetic modifications; or between epigenetic alterations and subsequent onset of cancer. Given that epigenetic modifications may play an important role in hormone-dependent cancers, it is essential to better understand the relationship between the hormonal environment and epigenetic modifications in both normal and disease states. In this review, we highlight several important studies which support the hypothesis that: hormonal perturbations early in life may result in epigenetic changes that may modify hormone receptor function, thereby contributing to an increased risk of developing hormone-related cancers.
Keywords: Epigenetic; Hormone; Cancer
Emerging roles for Rab family GTPases in human cancer by Wan Jie Chia; Bor Luen Tang ⁎ (pp. 110-116).
Members of the Ras- associated binding (Rab) family of small GTPases function as molecular switches regulating vesicular transport in eukaryotes cells. Their pathophysiological roles in human malignancies are less well-known compared to members of Ras and Rho families. Several members of the Rab family have, however, been shown to be aberrantly expressed in various cancer tissues. Recent findings have also revealed, in particular, Rab25 as a determinant of tumor progression and aggressiveness of epithelial cancers. Rab25 associates with α5β1 integrin, and enhances tumor cell invasion by directing the localization of integrin-containing vesicles to the leading edge of matrix invading pseudopodia. We summarized here recent findings on Rab25 and other Rabs implicated to be involved in a variety of human cancers, and discussed plausible mechanisms of how dysregulation of Rab expression could be tumorigenic or tumor suppressive.
Keywords: Cancer; Metastasis; Endocytosis; Rab; Signaling
Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: A review by Suzanne Hector ⁎; Jochen H.M. Prehn (pp. 117-129).
Colorectal cancer is a leading cause of cancer related mortality in the Western world. In recent years, combination 5-fluorouracil based adjuvant chemotherapy as first line treatment of this disease has led to improved disease free and overall survival. However drug resistance, both innate and acquired, remains an obstacle in the effective treatment of this disease. Apoptotic pathways are frequently altered in both tumor progression and drug resistance; therefore proteins associated with this pathway may have potential as prognostic biomarkers for this disease. Identification of clinical biomarkers that are able to identify patients who are more likely to respond to specific chemotherapy will lead to more personalized, effective, and less toxic therapy. This review focuses on the current status of apoptosis related proteins as biomarkers for colorectal cancer and discusses the possible application of systems approaches in this context.
Keywords: Colorectal cancer; Apoptosis; Biomarker; Prognosis
Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146 by Allal Ouhtit; Rajiv L. Gaur; Zakaria Y. Abd Elmageed; Augusta Fernando; Rajesh Thouta; Alison K. Trappey; Mohamed E. Abdraboh; Hassan I. El-Sayyad; Prakash Rao; Madhwa G.H. Raj (pp. 130-136).
CD146, also known as melanoma cell adhesion molecule or MCAM, is a key cell adhesion protein in vascular endothelial cell activity and angiogenesis. CD146 promotes tumor progression of many cancers including melanoma and prostate. Strikingly, its expression is frequently lost in breast carcinoma cells, and it may act as a suppressor of breast cancer progression. While upstream mechanisms regulating CD146 are well documented, our understanding of the downstream molecular events underlying its mode of action remains to be elucidated. This review aims to focus on the progress in understanding the signaling mechanisms and the functional relevance of CD146, a multifaceted molecule, in cancer with particular emphasis on its role in inhibiting breast cancer progression.
Keywords: Breast cancer; Angiogenesis; Signal transduction; CD146; Tumor suppressor
Rho GTPases in hepatocellular carcinoma by Florence Grise; Aurélien Bidaud; Violaine Moreau ⁎ (pp. 137-151).
Rho GTPases are major regulators of signal transduction pathways and play key roles in processes including actin dynamics, cell cycle progression, cell survival and gene expression, whose deregulation may lead to tumorigenesis. A growing number of in vitro and in vivo studies using tumor-derived cell lines, primary tumors and animal cancer models strongly suggest that altered Rho GTPase signaling plays an important role in the initiation as well as in the progression of hepatocellular carcinoma (HCC), one of the deadliest human cancers in the world. These alterations can occur at the level of the GTPases themselves or of one of their regulators or effectors. The participation into the tumorigenic process can occur either through the over-expression of one of these components which presents an oncogenic activity as illustrated with RhoA and C or through the attenuation of the expression of a component presenting tumor suppressor activity as for Cdc42 or the RhoGAP, DLC-1. Consequently, these observations reflect the heterogeneity and the complexity of liver carcinogenesis. Recently, pharmacological approaches targeting Rho GTPase signaling have been used in HCC-derived models with relative success but remain to be validated in more physiologically relevant systems. Therefore, therapeutic approaches targeting Rho GTPase signaling may provide a novel alternative for anti-HCC therapy.
Keywords: Rho GTPases; Hepatocellular carcinoma; Signaling
Role of B-RafV600E in differentiated thyroid cancer and preclinical validation of compounds against B-RafV600E by Carmelo Nucera; Melanie Goldfarb; Richard Hodin; Sareh Parangi (pp. 152-161).
B-RafV600E, an oncogenic protein kinase, is the most frequent genetic alteration in papillary thyroid carcinomas (PTC). PTC represents 80–90% of all thyroid cancers and over the past five years, more than 200 manuscripts have been published about the relationship between “B-RafV600E and thyroid cancer”. B-RafV600E genetically arises from a transversion point mutation (valine-to-glutamate substitution at amino acid residue-600, V600E) and leads to over activation of the mitogen-activated protein kinases (MAPK) signaling pathway. The MAPK pathway is essential for transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. In many cancers, including thyroid cancer, B-RafV600E appears to play a crucial role in cell proliferation, survival and de-differentiation. In thyroid cancer, the V600E mutation occurs with greater frequently in aggressive subtypes of PTC, and in individuals that present at advanced stages of disease with extra-thyroidal extension and/or lymph node metastases. B-RafV600E is considered a marker of aggressive disease in both PTC (>1 cm) and micro-PTC (≤1 cm), and interestingly, is associated with both loss of I-131 avidity and PTC recurrence. Though treatment of patients with thyroid cancer is usually successful and most patients are rendered disease-free, to date there are no effective therapies for patients with invasive, non-radioiodine sensitive tumors or metastatic disease. In this article we will review the relation between B-RafV600E and PTC, as well as both non-selective and selective pharmacological agents currently under investigation for treatment of B-RafV600E positive PTC.
Keywords: Differentiated thyroid cancer; Papillary thyroid cancer; Papillary thyroid microcarcinoma; Extrathyroidal extension; Wild-type B-Raf; B-Raf; V600E; MAP kinases; Compounds; Preclinical validations
Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show? by Stefan Kaluz; Milota Kaluzová; Shu-Yuan Liao; Michael Lerman; Eric J. Stanbridge (pp. 162-172).
Transcriptional activation by hypoxia is mediated by the hypoxia-inducible factor (HIF) via binding to the hypoxia-responsive element (HRE). Hypoxia in solid tumors associates with poorer outcome of the disease and reliable cellular markers of tumor hypoxia would represent a valuable diagnostic marker and a potential therapeutic target. In this category, carbonic anhydrase IX (CAIX) is one of the most promising candidates. Here, we summarize the knowledge about transcriptional regulation of CA9. The HRE is the central regulatory element in the CA9 promoter, whereas other elements are limited to lesser roles of amplification of signals received at the HRE. The analysis of known mechanisms of activation of CA9 reveals the prominent role of the HIF-1 pathway. Experimental paradigms with uncoupled HIF-1α stability and transcriptional activity (pericellular hypoxia, proteasomal inhibitor) provide evidence that CA9 expression monitors transcriptional activity of HIF-1, rather than the abundance of HIF-1α. Furthermore, these paradigms could provide a corollary to some of the apparently discordant cases (CAIX+, HIF-1α−) or (CAIX−, HIF-1α+) observed in vivo. In conclusion, the existing data support the notion that CA9, due to the unique structure of its promoter, is one of the most sensitive endogenous sensors of HIF-1 activity.
Keywords: Abbreviations; 2-OG; 2-oxoglutarate; CAD; C-terminal activation domain; CAIX; carbonic anhydrase IX; ERK; extracellular signal-regulated protein kinase; HBS; HIF-binding site; HIF; hypoxia-inducible factor; HRE; hypoxia-responsive element; FIH-1; factor inhibiting HIF-1; MOI; multiplicity of infection; NAD; N-terminal activation domain; ODDD; O; 2; -dependent degradation domain; PHDs; prolyl hydroxylase domain proteins; PI-3K; phosphatidylinositol 3-kinase; PIs; proteasomal inhibitors; PR; protected region; RCCC; renal clear cell carcinoma; VEGF; vascular endothelial growth factor; VHL; von Hippel–Lindau proteinCarbonic anhydrase IX; Transcriptional regulation; Hypoxia; Hypoxia-inducible factor