Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis

The exact role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian epithelial carcinoma (OEC) development has not been yet characterized. This prompted us to identify particular proteins to better understand the underlying mechanism. Total proteins from ovarian epithelial tumor (OET) cells treated with gonadotropins were analyzed by proteomics. Western blot and immunohistochemistry were used to validate the target protein (prohibitin) and to detect its expression in human ovarian tissue of serous tumors. As the results, prohibitin was found to be significantly up-regulated by LH, with a maximum of 2.5-fold increase at the concentration of 200 mIU/mL. The expression of prohibitin was steadily decreased from benign serous cystadenomas to borderline tumors and serous carcinomas (P < 0.0001). The difference between any two groups was significant (P < 0.001). Collectively, data from this study indicate that prohibitin is one LH-associated protein and it may be protective of ovarian cancer development and progression, supporting that LH may play an inhibitory role in ovarian tumorigenesis.     

The immune system and inflammation in breast cancer

During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.     

BRCA2 gene mutation in cancer

Breast cancer susceptibility gene 2 (BRCA2) is the main gene associated with hereditary breast cancers. However, a mutation in BRCA2 has also been found in other tumors, such as ovarian, pancreatic, thyroid, gastric, laryngeal, and prostate cancers. In this review, we discuss the biological functions of BRCA2 and the role of BRCA2 mutations in tumor progression and therapy.     

Role of the IGF axis in prostate cancer

The major issue currently being faced in the management of prostate cancer is the inability to distinguish between indolent prostate tumors that will not present clinically from more aggressive and metastatic prostate cancers that will impact on men's lives. Only a small proportion of prostate cancers can be accounted for by unmistakable hereditary cancer syndromes and the predominant contribution to the progression of most sporadic cancers is thought to be environmental, with nutrition having the greatest influence. Population studies have clearly implicated metabolic factors as contributors to disease progression and poor response to therapy. It is well established that the IGF system is key in regulating growth and metabolism and mediates the effects of nutrition on these processes. It consists of two ligands (IGF-I and IGF-II), two receptors [type 1 IGF-IR and IGF-II/mannose 6-phosphate receptor], and six high affinity IGF-binding proteins (IGFBP-1 to -6). This review provides evidence from in vitro, in vivo, clinical and epidemiology studies that indicates an important role for the IGF axis in the development of prostate cancer and the likely role that it plays in mediating the effects of nutrition on disease progression. We suggest that the IGF axis is central to understanding how lifestyle impacts on prostate cancer and we highlight this by describing numerous strategies being developed to target this axis.     

Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

We show here that elevated levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), as found in menopause or after ovariectomy, promote growth of human ovarian carcinoma by induction of tumor angiogenesis. Human epithelial ovarian cancer tumors progressed faster in ovariectomized mice. This induced growth could be attributed to the elevated levels of gonadotropins associated with loss of ovarian function because direct administration of gonadotropins also was effective in promoting tumor progression in vivo. On the other hand, gonadotropins had no direct effect on the proliferation of human ovarian cancer cells in vitro. Using MRI, we demonstrated that ovariectomy significantly (P < 0.02) induces neovascularization of human ovarian carcinoma spheroids implanted in nude mice. Moreover, conditioned medium of gonadotropin-treated human ovarian carcinoma cells showed increased mitogenic activity to bovine endothelial cells, and this activity could be blocked by neutralizing antibodies against luteinizing hormone and against vascular endothelial growth factor. Accordingly, gonadotropin stimulation resulted in a dose-dependent-induced expression of vascular endothelial growth factor in monolayer culture as well as in the outer proliferating cells of human ovarian cancer spheroids. These results demonstrate the significance of the elevated levels of gonadotropins, as found in menopause and in all ovarian cancer patients, on the progression of ovarian cancer and could explain the protective effect of estrogen replacement therapy. Based on these results, we suggest that hormonal therapy aimed at lowering the circulating levels of gonadotropins may possibly prolong remission in ovarian cancer by extending tumor dormancy.     

Paracrine and endocrine effects of adipose tissue on cancer development and progression

The past few years have provided substantial evidence for the vital role of the local tumor microenvironment for various aspects of tumor progression. With obesity and its pathophysiological sequelae still on the rise, the adipocyte is increasingly moving center stage in the context of tumor stroma-related studies. To date, we have limited insight into how the systemic metabolic changes associated with obesity and the concomitant modification of the paracrine and endocrine panel of stromal adipocyte-derived secretory products ("adipokines") influence the incidence and progression of obesity-related cancers. Here, we discuss the role of adipocyte dysfunction associated with obesity and its potential impact on cancer biology.     

Emerging roles of non-coding RNAs in gastric cancer: Pathogenesis and clinical implications

Gastric cancer is a leading cause of cancer-related deaths. However, the mechanisms underlying gastric carcinogenesis remain largely unclear. The association of non-coding RNAs(nc RNAs) with cancer has been widely studied during the past decade. In general, nc RNAs have been classified as small nc RNAs, including micro RNAs(mi RNAs), and long non-coding RNAs(lnc RNAs). Emerging evidence shows that mi RNAs and lnc RNAs play key roles in the formation and progression of many cancers. In this review, we focus on the regulation of mi RNAs and lnc RNAs in gastric cancer. mi RNAs and lnc RNAs appear to be involved in gastric tumor growth, invasion, and metastasis and in establishment of the gastric tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing mi RNAs and lnc RNAs as potential biomarkers and therapeutic targets for gastric cancer. Taken together, we summarize the emerging roles of nc RNAs in gastric cancer development and their possible clinical significance.     

Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets?

Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.     

Immune Response and the Tumor Microenvironment: How They Communicate to Regulate Gastric Cancer

Gastric cancer is the second most common cause of cancer-related death in the world. A growing body of evidence indicates that inflammation is closely associated with the initiation, progression, and metastasis of many tumors, including those of gastric cancer. In addition, approximately 60% of the world''s population is colonized by Helicobacter pylori, which accounts for more than 50% of gastric cancers. While the role of inflammation in intestinal and colonic cancers is relatively well defined, its role in stomach neoplasia is still unclear because of the limited access of pathogens to the acidic environment and the technical difficulties isolating and characterizing immune cells in the stomach, especially in animal models. In this review, we will provide recent updates addressing how inflammation is involved in gastric malignancies, and what immune characteristics regulate the pathogenesis of stomach cancer. Also, we will discuss potential therapeutics that target the immune system for the efficient treatment of gastric cancer.     

Expression and biological role of δ-catenin in human ovarian cancer

Objective

δ-Catenin is found to be involved in the progression of several human cancers. However, its expression pattern and biological roles in human ovarian cancers are not clear. In this study, we examined the expression pattern of δ-catenin in 149 ovarian cancer specimens. We also depleted and overexpressed δ-catenin expression in ovarian cancer cell lines and investigated its role in cell proliferation and invasion.

Methods

δ-Catenin expression was analyzed in 149 archived ovarian cancer specimens using immunohistochemistry. siRNA knockdown and plasmid transfection were performed in SKOV3, SW626, and OVCAR3 cell lines. MTT, colony formation assay, soft agar colony assay, and matrigel invasion assay were carried out to assess the role of δ-catenin in cell proliferation and invasion. We also performed cell cycle analysis in δ-catenin depleted and overexpressed cells. In addition, we examined the level of several cell cycle-related molecules using Western blot.

Results

Of the 149 patients in the study, 104 (69.7?%) showed δ-catenin overexpression. δ-catenin overexpression positively correlated with advanced FIGO stage. δ-Catenin depletion in ovarian cancer cell lines inhibited ovarian cancer cell proliferation and invasion. Depletion of δ-catenin also blocked cell cycle progression and downregulated cyclin D1 expression in ovarian cancer cells. Overexpression of δ-catenin enhanced cell proliferation, invasion, and upregulated cyclinD1 expression.

Conclusions

δ-Catenin is overexpressed in ovarian cancers and associated with advanced stage. Our data provide evidence that δ-catenin regulates the ovarian cancer cell proliferation, invasion, and cell cycle. δ-Catenin thus has potential as a therapeutic target.     

The role of inhibins and activins in prostate cancer pathogenesis

Successful prostate cancer diagnosis and management continue to provide challenges for the clinician. While interventions aimed at the containment of both early and late disease continue to fail in a significant number of patients, the search for answers must incorporate an analysis of the processes of normal and aberrant growth and development within the gland itself. Inhibin and its structurally related protein, activin, are members of the transforming-growth-factor beta (TGFbeta) superfamily. Originally identified as regulators of FSH, these proteins are now recognised to have widespread biological functions. This might be expected of proteins that are structurally homologous to TGFbeta itself, which is recognised to have regulatory roles in both normal and malignant prostate tissue. The aim of this review is to examine the relationship between inhibins, activins and their related proteins and the development of prostate cancer. The homology with TGF, the pluripotent effects of activin on various tissues and the roles for inhibins in ovarian cancer make activins and inhibins candidate growth factors for involvement at multiple sites in the progression from benign disease to cancer. In compiling this review, we aim to delineate the changes in inhibins and activins in this pathway and in doing so implicate their potential roles in the progression of carcinogenesis. We will compare the changes in inhibin and its related proteins in prostate cancer to those that are known in ovarian cancer. We will discuss the similarities and differences between the putative role of activins and TGFbeta in prostate carcinogenesis. The importance of this review lies in demonstrating that inhibin, an endocrine hormone, and its related proteins may contribute to endocrine-related cancers, such as that of the prostate gland.     

Obesity and Cancer: An Angiogenic and Inflammatory Link

With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti‐angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti‐diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.     

Pericytes and vessel maturation during tumor angiogenesis and metastasis

Despite promising results in preclinical and clinical studies, the therapeutic efficacy of antiangiogenic therapies has been restricted by a narrow focus on inhibiting the growth of endothelial cells. Other cell types in the tumor stroma are also critical to the progression of cancer, including mural cells. Mural cells are vascular support cells that range in phenotype from pericytes to vascular smooth muscle cells. Although the role of pericytes and pericyte‐like cells in the pathophysiology of cancer is still unclear, evidence indicates that aberrations in pericyte–endothelial cell signaling networks could contribute to tumor angiogenesis and metastasis. The purpose of this review is to evaluate critically recent evidence on the role of pericytes in tumor biology and discuss potential therapeutic targets for anticancer intervention. Am. J. Hematol. 85:593–598, 2010. © 2010 Wiley‐Liss, Inc.     

Clinical review 158: Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer

One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progress despite surgery, radioiodine, and T(4) suppression of TSH. As knowledge of thyroid cancer biology improves, the potential exists to develop compounds targeted to treat thyroid cancers that do not respond to traditional therapy. Recently, the development of therapies targeted against specific molecular pathways involved in cancer progression has resulted in dramatic responses in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers. A number of compounds are currently being evaluated in clinical trials that alter pathways involved thyroid cancer, and several of these agents have been tested in thyroid cancer in vitro and in vivo. In this review we will discuss the mechanisms of action and preclinical/clinical data for several of these compounds that have the potential to play an important role in the management of thyroid cancer in the future.     

Lymphangiogenesis: A new player in cancer progression

Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymph...     

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.     

Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination

Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer （CRC）, observation of heterogeneous β-catenin distribution and epithelial-mesenchymal transition （EMT） at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.     

Sex-steroid regulation of vascular endothelial growth factor in breast cancer

Angiogenesis is a key event, which occurs in both normal and pathological expansion of tissues and provides the nourishment necessary for growth. The role of angiogenic growth factors in breast pathology is rapidly gaining recognition since scientists and clinicians realized that these factors could function as molecular targets event 550 209822 for controlling tumor expansion. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. Although significant advances have been made in understanding the sex-steroid-dependent regulation of this key factor, the role of VEGF in controlling breast tumors is not well understood. In this review, I discuss recent studies describing the role of the female sex steroids estrogens and progestins in the regulation of VEGF in breast cancer cells. Furthermore, I present a summary of recent studies from other biological systems (mainly focused on tumor biology) directed towards providing us with a better understanding of the regulation of classical VEGF and VEGF receptors. I propose that by extending such studies we will gain deeper insights into how we might combat the progression of breast cancer by controlling hormone-dependent angiogenesis within tumor tissue. I believe that information gained from such studies will permit us to target angiogenic growth factors and their initiated signal transduction pathways in a more precise and selective manner, and thereby to control the formation of new blood vessels that fuel the rapid growth of breast tumors. Finally, it is my hope that the concepts discussed here will help elucidate molecular targets in the hormone-dependent angiogenesis pathway that will ultimately allow us to overcome anti-hormone resistance and to provide insights into how we might pursue the concept of chemoprevention by considering 'angioprevention' as the end point.