Beta-adrenergic receptors in cancer: therapeutic implications

The beta-adrenergic receptors transduce catecholamine signals to the G protein, which through a cascade of chemical reactions in cells generates highly specific parallel signals. The beta2-adrenergic receptor (ADRB2) is the most involved in the carcinogenic processes. Previous studies have determined the relationship of ADRB2 with various aspects related to cancer. Basically, it seems to be related with cell proliferation and apoptosis, chemotaxis, development of metastasis and tumor growth, and angiogenesis. The purpose of this review is to update the implications of these receptors in the pathogenesis of cancer and study the possible application of agonist drugs and/or antagonists in antitumor therapy.     

Tumor-specific demethylation of heterochromatic repetitive DNA in gastrointestinal cancer

DNA methylation appears to play an important role in both physiological and experimentally modified gene expression. Alterations in DNA methylation have been described in animal tumour models, in transformed cells and tumour cell lines, usually for single copy DNA sequences. By applying the isoschizomeres HpaII and MspI the methylation status of two classes of repetitive sequences (D22Z2 - a member of the alphoid repeats and D22Z3 which belongs to the HinfI repeats) in colon and stomach carcinoma were tested. A strong demethylation of both types of repetitive sequences in stomach carcinoma in comparison to healthy stomach mucosa was detected. In colon carcinoma, only minor signs of demethylation occured for the same repetitive DNA.     

Angiogenesis in colorectal cancer: prognostic and therapeutic implications

Angiogenesis is important for tumor growth and metastasis. This account reviews the clinicopathological studies conducted in the field of angiogenesis in colorectal cancer, the methods of assessing vascular-related characteristics in tissue sections and provides a background for the usefulness of antiangiogenic policies along with chemotherapy and radiotherapy. Highly angiogenic colorectal tumors are associated with aggressive histopathological features and poor patients' survival. Similarly, factors stimulating angiogenesis, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP), and others, are commonly related to increased vascular density (VD) and, therefore, to an unfavorable clinical course. Anti-VEGF agents have improved prognosis in patients with metastatic colorectal cancer, when added to standard chemotherapy. It is expected that, in addition to adjuvant chemotherapy and radiotherapy, agents blocking the stimulatory effect of VEGF on endothelial cells would prove beneficial to the patient.     

Triple negative breast cancer: therapeutic and prognostic implications

Triple negative breast cancers (TNBC) lack oestrogen receptor (ER), progesterone receptor (PR), nor over-express human epidermal growth factor receptor 2 (HER2). Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinic-pathologic features and risk factors when compared to women with other subtypes of breast cancer. They are associated with poor prognosis, as defined by low five-year survival. To date many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings. Targeted therapy options involving PARP1 and EGFR inhibition, are currently in different phases of development and will hopefully change the paradigm of how patients with TNBC are treated. The present commentary aims to summarize the latest findings on chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.     

Angiogenesis and lung cancer: prognostic and therapeutic implications.

Lung cancer is the most common cause of cancer death worldwide, with most patients dying with metastatic disease. The prognosis for the majority of patients remains poor. It is evident that advances in the treatment of this and other tumor types will require new approaches, and recent research has focused on molecular-targeted therapies. A key therapeutic strategy is inhibition of specific processes essential for tumor vascular development (a concept known to be beneficial in colorectal cancer) and a range of such antiangiogenic agents are currently in development. The most promising of these target the proangiogenic vascular endothelial growth factor (VEGF), either by preventing VEGF-receptor binding or inhibiting downstream receptor signaling. However, other more direct approaches against tumor vasculature are also in development. Since antiangiogenic agents often exert an indirect, cytostatic effect, many are being evaluated in combination with conventional chemotherapies in order to optimize the anticancer effects of both strategies. Additionally, the combination of several antiangiogenic agents is also being explored. This has become possible given the large number of agents currently available. As part of this evaluation process, the assessment of surrogate markers of target inhibition and treatment effect is ongoing in the hope of identifying reliable surrogate markers to aid the development of this new generation of anticancer agents.     

Biological subtypes of breast cancer: Prognostic and therapeutic implications

Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. Traditional classification systems regarding biological characteristics may have limitations for patient-tailored treatment strategies. Tumors with similar clinical and pathological presentations may have different behaviors. Analyses of breast cancer with new molecular techniques now hold promise for the development of more accurate tests for the prediction of recurrence. Gene signatures have been developed as predictors of response to therapy and protein gene products that have direct roles in driving the biology and clinical behavior of cancer cells are potential targets for the development of novel therapeutics. The present review summarizes current knowledge in breast cancer molecular biology, focusing on novel prognostic and predictive factors.     

Ovarian cancer stem cell markers: Prognostic and therapeutic implications

Cancer stem cells are rare chemotherapy resistant cells within a tumor which can serve to populate the bulk of a tumor with more differentiated daughter cells and potentially contribute to recurrent disease. Ovarian cancer is a disease for which at the time of initial treatment we can obtain complete clinical remission in the majority of patients. Unfortunately, most will relapse and succumb to their disease. This clinical course is in line with the cancer stem cell model. In the past 5 years a significant amount of work has been done to identify cells with characteristics of ovarian cancer stem cells. This review will focus specifically on the markers used to define human ovarian cancer stem cells, the prognostic implications of the expression of these cancer stem cell markers in patient’s primary tumors, and the potential of these cancer stem cell markers to serve as therapeutic targets.     

GRP78 induction in cancer: therapeutic and prognostic implications

Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of GRP78/BiP, a major endoplasmic reticulum chaperone with Ca(2+)-binding and antiapoptotic properties. GRP78 promotes tumor proliferation, survival, metastasis, and resistance to a wide variety of therapies. Thus, GRP78 expression may serve as a biomarker for tumor behavior and treatment response. Combination therapy suppressing GRP78 expression may represent a novel approach toward eradication of residual tumors. Furthermore, the recent discovery of GRP78 on the cell surface of cancer cells but not in normal tissues suggests that targeted therapy against cancer via surface GRP78 may be feasible.     

Angiogenesis in colorectal cancer: therapeutic implications and future directions

This article discusses the therapeutic implications and future directions of angiogenesis in colorectal cancer.     

SETDB1 in cancer: overexpression and its therapeutic implications

SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1, ESET, KMT1E) is a H3K9 methyltransferase involved in gene silencing. In recent years, SETDB1 has been implicated as an oncogene in various cancers, highlighting a critical need to better understand the mechanisms underlying SETDB1 amplification, overexpression, and activation. In the following review, we first examine the history of SETDB1, starting from its discovery in 1999 and ending with recent findings. We follow with an outline of the structure and subcellular location of SETDB1, as well as potential mechanisms for regulation of its nuclear transport. Subsequently, we introduce SETDB1’s various functions, including its roles in promyelocytic leukemia nuclear body (PML-NB) formation, the methylation and activation of Akt, the silencing of the androgen receptor (AR) gene, retroelement silencing, the inhibition of tumor suppressor p53, and its role in promoting intestinal differentiation and survival. The Cancer Cell Line Encyclopedia (CCLE) screened SETDB1 dependency in 796 cancer cell lines, identifying SETDB1 as a common essential gene in 531 of them, demonstrating that SETDB1 expression is critical for the survival of the majority of cancers. Therefore, we provide a detailed review of the oncogenic effects of SETDB1 overexpression in breast cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, acute myeloid leukemia, glioma, melanoma, pancreatic ductal adenocarcinoma, liver cancer, nasopharyngeal carcinoma, gastric carcinoma, and endometrial cancer. Accordingly, we review several methods that have been used to target SETDB1, such as using Mithramycin A, Mithralog EC-8042, 3’-deazaneplanocin A (DZNep), and paclitaxel. Finally, we conclude by highlighting remaining gaps in knowledge and challenges surrounding SETDB1. Ultimately, our review captures the wide scope of findings on SETDB1’s history, function, its implications in cancer, and provides suggestions for future research in the field.     

Origins of breast cancer subtypes and therapeutic implications

This Review summarizes and evaluates the current evidence for the cellular origins of breast cancer subtypes identified by different approaches such as histology, molecular pathology, genetic and gene-expression analysis. Emerging knowledge of the normal breast cell types has led to the hypothesis that the subtypes of breast cancer might arise from mutations or genetic rearrangements occurring in different populations of stem cells and progenitor cells. We describe the common distinguishing features of these breast cancer subtypes and explain how these features relate both to prognosis and to selection of the most appropriate therapy. Recent data indicate that breast tumors may originate from cancer stem cells. Consequently, inhibition of stem-cell self-renewal pathways should be explored because of the likelihood that residual stem cells might be resistant to current therapies.     

Metabolic alterations in cancer cells and therapeutic implications

Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.     

Lymphadenectomy in gastric cancer: prognostic role and therapeutic implications.

AIMS: Surgeons involved in the treatment of gastric cancer are interested in the extent of lymphadenectomy as the latter may not only influence the reliability of the tumour, node and metastasis classification but also be relevant for the long-term oncological outcome. The purpose of the study was to evaluate the prognostic role of the number of resected lymph nodes (as an indicator of the scope of lymphadenectomy) and of the number of metastatic lymph nodes on the long-term mortality for all causes and to provide clinicians with estimates of predictive survival probabilities. METHODS: The study involved 615 cancer patients subjected to a curative (R0) subtotal or total gastrectomy in a randomized Italian trial. According to the trial protocol, a D2 lymphadenectomy had been advised. The number of resected and metastatic lymph nodes was analysed as a continuous variable in multiple Cox models. RESULTS: There was no difference in operative mortality (about 1.8%) according to the number of lymph nodes in the specimen (< or =15, 16-25, >25). The risk of long-term death for all causes tended to decrease with increasing number of resected lymph nodes up to about 25, and then could be considered stable for wider lymphadenectomies. An increasing risk of death for all causes was associated with an increasing number of metastatic lymph nodes; the risk could be considered stable for more than 20 metastatic lymph nodes. CONCLUSIONS: A lymphadenectomy including more than 25 lymph nodes is suggested, provided that there is a low risk of operative mortality.     

MicroRNA in pancreatic cancer: Pathological,diagnostic and therapeutic implications

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules of 17–25 nucleotides (nt) in length, predicted to control the activity of about 30% of all protein-coding genes in mammals. Altered expressions of miRNAs are reported in various cancers and may associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. Recent reports showed that deregulation of miRNA contribute to tumor development and progression and hence, have diagnostic and prognostic value in several human malignancies. This review discusses the current status of miRNA in pancreatic cancer development, progression, diagnosis, and therapy.