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Endocrine side effects of cancer immunotherapy
Immune checkpoint inhibitors have recently become a cornerstone for the treatment of different advanced cancers. These drugs, represented mainly by monoclonal antibodies anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) and anti-PD-1 ligand molecules (PD-L1 and L2), have the ability to reactivate the immune system against tumor cells, but can also trigger a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). In particular, there are a number of endocrine-related irAEs. Current data from clinical trials show increased incidence of hypophysitis with CTLA4...
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Cukier, P., Santini, F. C., Scaranti, M., Hoff, A. O. Tags: Thematic Review Source Type: research

Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission
The incidence of thyroid cancers has been steadily increasing worldwide over the past few decades. Although five-year survival rates for differentiated thyroid cancers are upwards of 90%, clinical outcomes for patients with undifferentiated, recurrent and/or metastatic disease are often dismal despite conventional interventions. As such, there is a demand for novel treatment options. Cancer immunotherapy represents the ultimate form of personalized medicine by leveraging the specificity and potency of a patient’s immune system to kill their tumor. The thyroid cancer microenvironment is rich in immunological cells, ma...
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Mould, R. C., van Vloten, J. P., AuYeung, A. W. K., Karimi, K., Bridle, B. W. Tags: Thematic Review Source Type: research

Androgen deprivation and immunotherapy for the treatment of prostate cancer
Prostate cancer is the most common newly diagnosed malignancy in men, and the second most common cause of cancer-related death in the United States. The primary treatment for recurrent prostate cancer is androgen deprivation, and this therapy is typically continued lifelong for patients with metastatic prostate cancer. Androgens and androgen deprivation have profound effects on the immune system, a finding that has become more appreciated in an era where immune-based treatments for cancer are being increasingly explored. Preclinical studies suggest that androgen deprivation could potentially positively or negatively affect...
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Gamat, M., McNeel, D. G. Tags: Thematic Review Source Type: research

The role of the tumour microenvironment in immunotherapy
Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current know...
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Gasser, S., Lim, L. H. K., Cheung, F. S. G. Tags: Thematic Review Source Type: research

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way
We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged. (Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Cunha, L. L., Marcello, M. A., Rocha-Santos, V., Ward, L. S. Tags: Thematic Review Source Type: research

Cancer immunotherapy: unique perspectives for endocrine-related cancers
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - November 2, 2017 Category: Endocrinology Authors: Ngeow, J. Y. Y., Ward, L. S. Tags: Editorials Source Type: research

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype
We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro, human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability...
Source: Endocrine-Related Cancer - October 20, 2017 Category: Endocrinology Authors: Ashtekar, A., Huk, D., Magner, A., La Perle, K., Zhang, X., Piruat, J. I., Lopez-Barneo, J., Jhiang, S. M., Kirschner, L. S. Tags: Research Source Type: research

TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis
Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT kno...
Source: Endocrine-Related Cancer - October 9, 2017 Category: Endocrinology Authors: Wang, H., Zhou, R., Sun, L., Xia, J., Yang, X., Pan, C., Huang, N., Shi, M., Bin, J., Liao, Y., Liao, W. Tags: Research Source Type: research

Circulating steroid hormone variations throughout different stages of prostate cancer
Steroid hormones play a central role in the maintenance and progression of prostate cancer. The androgen receptor is the primary driver of tumor cell proliferation and is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of this pathway through medical or surgical castration improves survival in the majority of advanced prostate cancer patients. However, conversion of adrenal androgen precursors and alternative steroidogenic pathways have been found to contribute to tumor progression and resistance to treatment. The emergence of highly accurate detection methods allows us to study steroid...
Source: Endocrine-Related Cancer - October 9, 2017 Category: Endocrinology Authors: Snaterse, G., Visser, J. A., Arlt, W., Hofland, J. Tags: Review Source Type: research

Molecular and phenotypic evaluation of a novel germline TMEM127 mutation with an uncommon clinical presentation
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - September 27, 2017 Category: Endocrinology Authors: Deng, Y., Flores, S. K., Cheng, Z., Qin, Y., Schwartz, R. C., Malchoff, C., Dahia, P. L. M. Tags: Research Letter Source Type: research

Dynamic risk stratification in the follow-up of thyroid cancer: what is still to be discovered in 2017?
In conclusion, dynamic risk stratification allows for better prediction of the risk of recurrence in thyroid carcinoma, what has been demonstrated in numerous retrospective analyses. However, the validation of this approach in prospective studies seems to be our task for near future. (Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - September 19, 2017 Category: Endocrinology Authors: Krajewska, J., Chmielik, E., Jarząb, B. Tags: Review Source Type: research

Role of thyroid hormones in the neoplastic process: an overview
Thyroid hormones (TH) are critical regulators of several physiological processes, which include development, differentiation and growth in virtually all tissues. In past decades, several studies have shown that changes in TH levels caused by thyroid dysfunction, disruption of deiodinases and/or thyroid hormone receptor (TR) expression in tumor cells, influence cell proliferation, differentiation, survival and invasion in a variety of neoplasms in a cell type-specific manner. The function of THs and TRs in neoplastic cell proliferation involves complex mechanisms that seem to be cell specific, exerting effects via genomic a...
Source: Endocrine-Related Cancer - September 19, 2017 Category: Endocrinology Authors: Goemann, I. M., Romitti, M., Meyer, E. L. S., Wajner, S. M., Maia, A. L. Tags: Review Source Type: research

Medical ovariectomy in menopausal breast cancer patients with high testosterone levels: a further step toward tailored therapy
Five years of adjuvant therapy with anti-estrogens reduce the incidence of disease progression by about 50% in estrogen receptor-positive breast cancer patients, but late relapse can still occur after anti-estrogens have been discontinued. In these patients, excessive androgen production may account for renewed excessive estrogen formation and increased risks of late relapse. In the 50% of patients who do not benefit with anti-estrogens, the effect of therapy is limited by de novo or acquired resistance to treatment. Androgen receptor and epidermal growth factor receptor overexpression are recognized mechanisms of endocrin...
Source: Endocrine-Related Cancer - September 19, 2017 Category: Endocrinology Authors: Secreto, G., Muti, P., Sant, M., Meneghini, E., Krogh, V. Tags: Commentary Source Type: research

The future: surgical advances in MEN1 therapeutic approaches and management strategies
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim o...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Sadowski, S. M., Cadiot, G., Dansin, E., Goudet, P., Triponez, F. Tags: Thematic Review Source Type: research

Management impact: effects on quality of life and prognosis in MEN1
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrine tumor syndrome, caused by inactivating mutations of the MEN1 tumor suppressor gene at 11q13 locus, which predisposes to develop tumors in target neuroendocrine tissues. As the positional cloning and identification of the causative gene in 1997, genetic diagnosis, by the sequencing-based research of gene mutations, has become an important tool in the early and differential diagnosis of the disease. Application of the genetic test, in MEN1 index cases and in first-degree relatives of mutated patients, has been constantly increasing during the last ...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Marini, F., Giusti, F., Tonelli, F., Brandi, M. L. Tags: Thematic Review Source Type: research

The future: diagnostic and imaging advances in MEN1 therapeutic approaches and management strategies
Prospective randomized data are lacking, but current clinical expert guidelines recommend annual screening examinations, including laboratory assessments and various imaging modalities (e.g. CT, MRI, scintigraphy and EUS) for patients with multiple endocrine neoplasia type 1 (MEN1). Routine screening is proposed to detect and localize neuroendocrine manifestations as early as possible. The goal is timely intervention to improve quality of life and to increase life expectancy by preventing the development of life-threatening hormonal syndromes and/or metastatic disease. In recent years, some studies compared different and n...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Manoharan, J., Albers, M. B., Bartsch, D. K. Tags: Thematic Review Source Type: research

MEN4 and CDKN1B mutations: the latest of the MEN syndromes
Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations o...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Alrezk, R., Hannah-Shmouni, F., Stratakis, C. A. Tags: Thematic Review Source Type: research

The future: medical advances in MEN1 therapeutic approaches and management strategies
Multiple endocrine neoplasia type 1 is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors and tumors of the anterior pituitary gland. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality. Causes of death nowadays have shifted toward local or metastatic progression of malignant neuroendocrine tumors. In early cohorts, complications like peptic ulcers in gastrinoma, r...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: van Leeuwaarde, R. S., de Laat, J. M., Pieterman, C. R. C., Dreijerink, K., Vriens, M. R., Valk, G. D. Tags: Thematic Review Source Type: research

Animal models of MEN1
Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which ...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Mohr, H., Pellegata, N. S. Tags: Thematic Review Source Type: research

Epigenetic regulation by the menin pathway
There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of meni...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Feng, Z., Ma, J., Hua, X. Tags: Thematic Review Source Type: research

Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1
Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next-generation sequencing has enabled studying genome-wide dynamics of chromatin ...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Dreijerink, K. M. A., Timmers, H. T. M., Brown, M. Tags: Thematic Review Source Type: research

The future: genetics advances in MEN1 therapeutic approaches and management strategies
The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous lo...
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Agarwal, S. K. Tags: Thematic Review Source Type: research

Happy 20th anniversary MEN1: from positional cloning to gene function restoration
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - September 12, 2017 Category: Endocrinology Authors: Weber, F., Mulligan, L. M. Tags: Editorials Source Type: research

The microenvironment induces collective migration in SDHB-silenced mouse pheochromocytoma spheroids
Pheochromocytomas (Pheos) and paragangliomas (PGLs) are neuroendocrine tumors. Approximately 30–40% of Pheos/PGLs are due to germline mutations in one of the susceptibility genes, including those encoding the succinate dehydrogenase subunits A-D (SDHA-D). Up to 2/3 of patients affected by SDHB mutated Pheo/PGL develop metastatic disease with no successful cure at present. Here, for the first time, we evaluated the effects of SDHB silencing in a three dimension (3D) culture using spheroids of a mouse Pheo cell line silenced or not (wild type/wt/control) for the SDHB subunit. We investigated the role of the microenviro...
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: D'Antongiovanni, V., Martinelli, S., Richter, S., Canu, L., Guasti, D., Mello, T., Romagnoli, P., Pacak, K., Eisenhofer, G., Mannelli, M., Rapizzi, E. Tags: Research Source Type: research

Differences in miRNA expression profiles between wild-type and mutated NIFTPs
Noninvasive encapsulated follicular variants of papillary thyroid carcinomas have been recently reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). NIFTPs exhibit a behavior that is very close to that of follicular adenomas but different from the infiltrative and invasive follicular variants of papillary thyroid carcinomas (FVPTCs). The importance of miRNAs to carcinogenesis has been reported in recent years. miRNAs seem to be promising diagnostic and prognostic molecular markers for thyroid cancer, and the combination of miRNA expression and mutational status might impro...
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: Denaro, M., Ugolini, C., Poma, A. M., Borrelli, N., Materazzi, G., Piaggi, P., Chiarugi, M., Miccoli, P., Vitti, P., Basolo, F. Tags: Research Source Type: research

Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas
This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogenei...
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: Murakami, M., Yoshimoto, T., Nakabayashi, K., Nakano, Y., Fukaishi, T., Tsuchiya, K., Minami, I., Bouchi, R., Okamura, K., Fujii, Y., Hashimoto, K., Hata, K.-i., Kihara, K., Ogawa, Y. Tags: Research Source Type: research

OP449 inhibits breast cancer growth without adverse metabolic effects
Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (P
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: Shlomai, G., Zelenko, Z., Antoniou, I. M., Stasinopoulos, M., Tobin-Hess, A., Vitek, M. P., LeRoith, D., Gallagher, E. J. Tags: Research Source Type: research

Acromegaly at diagnosis in 3173 patients from the Liege Acromegaly Survey (LAS) Database
Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females ...
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: Petrossians, P., Daly, A. F., Natchev, E., Maione, L., Blijdorp, K., Sahnoun-Fathallah, M., Auriemma, R., Diallo, A. M., Hulting, A.-L., Ferone, D., Hana, V., Filipponi, S., Sievers, C., Nogueira, C., Fajardo-Montanana, C., Carvalho, D., Hana, V., Stalla, Tags: Research Source Type: research

Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance
Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which stu...
Source: Endocrine-Related Cancer - August 22, 2017 Category: Endocrinology Authors: Zabkiewicz, C., Resaul, J., Hargest, R., Jiang, W. G., Ye, L. Tags: Review Source Type: research

Acromegaly is associated with increased cancer risk: a survey in Italy
It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 wom...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Terzolo, M., Reimondo, G., Berchialla, P., Ferrante, E., Malchiodi, E., De Marinis, L., Pivonello, R., Grottoli, S., Losa, M., Cannavo, S., Ferone, D., Montini, M., Bondanelli, M., De Menis, E., Martini, C., Puxeddu, E., Velardo, A., Peri, A., Faustini-Fu Tags: Research Source Type: research

Allosteric alterations in the androgen receptor and activity in prostate cancer
Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or mor...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Uo, T., Plymate, S. R., Sprenger, C. C. Tags: Review Source Type: research

Fighting tubulin-targeting anticancer drug toxicity and resistance
Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD eff...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Visconti, R., Grieco, D. Tags: Thematic Review Source Type: research

Consequences of mitotic slippage for antimicrotubule drug therapy
Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells ‘slip’ to the next in...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Cheng, B., Crasta, K. Tags: Thematic Review Source Type: research

Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic
Anti-mitotic cancer drugs include classic microtubule-targeting drugs, such as taxanes and vinca alkaloids, and the newer spindle-targeting drugs, such as inhibitors of the motor protein; Kinesin-5 (aka KSP, Eg5, KIF11); and Aurora-A, Aurora-B and Polo-like kinases. Microtubule-targeting drugs are among the first line of chemotherapies for a wide spectrum of cancers, but patient responses vary greatly. We still lack understanding of how these drugs achieve a favorable therapeutic index, and why individual patient responses vary. Spindle-targeting drugs have so far shown disappointing results in the clinic, but it is possib...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Shi, J., Mitchison, T. J. Tags: Thematic Review Source Type: research

Targeting mitotic pathways for endocrine-related cancer therapeutics
A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an ever-expanding catalog of proteins that orchestrate, participate and coordinate in the exquisite processes of spindle formation, chromosome dynamics and the formation and regulation of kinetochore microtubule attachments. Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers, but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable com...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Agarwal, S., Varma, D. Tags: Thematic Review Source Type: research

Centrosome amplification: a suspect in breast cancer and racial disparities
The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN) and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro, in vivo and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential ‘hit’ in multistep tumorigenesis, and in some others, non-tumorigenic. However, in vivo d...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Ogden, A., Rida, P. C. G., Aneja, R. Tags: Thematic Review Source Type: research

Germline mutation contribution to chromosomal instability
Genomic instability is a feature of cancer that fuels oncogenesis through increased frequency of genetic disruption, leading to loss of genomic integrity and promoting clonal evolution as well as tumor transformation. A form of genomic instability prevalent across cancer types is chromosomal instability, which involves karyotypic changes including chromosome copy number alterations as well as gross structural abnormalities such as transversions and translocations. Defects in cellular mechanisms that are in place to govern fidelity of chromosomal segregation, DNA repair and ultimately genomic integrity are known to contribu...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Chan, S. H., Ngeow, J. Tags: Thematic Review Source Type: research

Role of chromosomal instability in cancer progression
Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell’s genetic material – chromosomes – during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses:...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: McClelland, S. E. Tags: Thematic Review Source Type: research

50 years on ... the discovery of tubulin continues to advance cancer treatment
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Crasta, K., Aneja, R. Tags: Editorials Source Type: research

Lessons from bacterial homolog of tubulin, FtsZ for microtubule dynamics
FtsZ, a homolog of tubulin, is found in almost all bacteria and archaea where it has a primary role in cytokinesis. Evidence for structural homology between FtsZ and tubulin came from their crystal structures and identification of the GTP box. Tubulin and FtsZ constitute a distinct family of GTPases and show striking similarities in many of their polymerization properties. The differences between them, more so, the complexities of microtubule dynamic behavior in comparison to that of FtsZ, indicate that the evolution to tubulin is attributable to the incorporation of the complex functionalities in higher organisms. FtsZ an...
Source: Endocrine-Related Cancer - August 14, 2017 Category: Endocrinology Authors: Battaje, R. R., Panda, D. Tags: Thematic Review Source Type: research

Hashimotos thyroiditis predicts outcome in intrathyroidal papillary thyroid cancer
Hashimoto’s thyroiditis (HT) seems to have favourable prognostic impact on papillary thyroid cancer (PTC), but data were obtained analysing all disease stages. Given that HT-related microenvironment involves solely the thyroid, we aimed to assess the relationship between HT, as detected through pathological assessment, and outcome in intrathyroidal PTC. This was a multicentre, retrospective, observational study including 301 PTC with no evidence of extrathyroidal disease. Primary study endpoint was the rate of clinical remission. Auxiliary endpoint was recurrence-free survival (RFS). HT was detected in 42.5% of the c...
Source: Endocrine-Related Cancer - August 7, 2017 Category: Endocrinology Authors: Marotta, V., Sciammarella, C., Chiofalo, M. G., Gambardella, C., Bellevicine, C., Grasso, M., Conzo, G., Docimo, G., Botti, G., Losito, S., Troncone, G., De Palma, M., Giacomelli, L., Pezzullo, L., Colao, A., Faggiano, A. Tags: Research Source Type: research

Progression-free survival as a surrogate endpoint in advanced neuroendocrine neoplasms
In oncology clinical trials, overall survival (OS) is considered the gold standard outcome measure. In phase III trials for neuroendocrine neoplasms (NENs), however, progression-free survival (PFS) is more frequently used, as NENs are relatively rare and indolent neoplasms. But this surrogacy of PFS for OS has never been systematically validated. We, therefore, performed a literature-based analysis of phase II and III trials for NENs to evaluate the correlation between PFS and OS in NENs treated with medical treatment. We identified phase II and III clinical trials of medical treatment for advanced NENs based on a systemat...
Source: Endocrine-Related Cancer - August 7, 2017 Category: Endocrinology Authors: Imaoka, H., Sasaki, M., Takahashi, H., Hashimoto, Y., Ohno, I., Mitsunaga, S., Watanabe, K., Umemoto, K., Kimura, G., Suzuki, Y., Ikeda, M. Tags: Research Source Type: research

Genetic and epigenetic drivers of neuroendocrine tumours (NET)
Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution i...
Source: Endocrine-Related Cancer - August 7, 2017 Category: Endocrinology Authors: Di Domenico, A., Wiedmer, T., Marinoni, I., Perren, A. Tags: Review Source Type: research

Expression and mutational status of USP8 in tumors causing ectopic ACTH secretion syndrome
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - August 7, 2017 Category: Endocrinology Authors: Perez-Rivas, L. G., Osswald, A., Knosel, T., Lucia, K., Schaaf, C., Hristov, M., Fazel, J., Kirchner, T., Beuschlein, F., Reincke, M., Theodoropoulou, M. Tags: Research Letter Source Type: research

New HIF2{alpha} inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas
Two recent independent studies published in Nature show robust responses of clear cell renal cell carcinoma (ccRCC) cell lines, preclinical ccRCC xenograft models and, remarkably, a patient with progressive ccRCC despite receiving multiple lines of treatment, to the long-awaited, recently developed inhibitors of hypoxia-inducible factor 2-alpha (HIF2α). This commentary published in Endocrine-Related Cancer is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations ha...
Source: Endocrine-Related Cancer - August 7, 2017 Category: Endocrinology Authors: Toledo, R. A. Tags: Commentary Source Type: research

Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF
Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent repor...
Source: Endocrine-Related Cancer - July 31, 2017 Category: Endocrinology Authors: Imruetaicharoenchoke, W., Fletcher, A., Lu, W., Watkins, R. J., Modasia, B., Poole, V. L., Nieto, H. R., Thompson, R. J., Boelaert, K., Read, M. L., Smith, V. E., McCabe, C. J. Tags: Research Source Type: research

Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas
Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however...
Source: Endocrine-Related Cancer - July 24, 2017 Category: Endocrinology Authors: Formosa, R., Borg, J., Vassallo, J. Tags: Research Source Type: research

A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations...
Source: Endocrine-Related Cancer - July 24, 2017 Category: Endocrinology Authors: Dumanski, J. P., Rasi, C., Bjorklund, P., Davies, H., Ali, A. S., Gronberg, M., Welin, S., Sorbye, H., Gronbaek, H., Cunningham, J. L., Forsberg, L. A., Lind, L., Ingelsson, E., Stalberg, P., Hellman, P., Tiensuu Janson, E. Tags: Research Source Type: research

Estradiol for the mitigation of adverse effects of androgen deprivation therapy
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. Conventional endocrine treatment for PCa leads to global sex steroid deprivation. The ensuing severe hypogonadism is associated with well-documented adverse effects. Recently, it has become apparent that many of the biological actions attributed to androgens in men are in fact not direct, but mediated by estradiol. Available evidence supports a primary role for estradiol in vasomotor stability, skeletal maturation and maintenance, and prevention of fat accumulation. Hence there has been interest in revisiting estradiol as a treatment for PCa. Potent...
Source: Endocrine-Related Cancer - July 24, 2017 Category: Endocrinology Authors: Russell, N., Cheung, A., Grossmann, M. Tags: Review Source Type: research

STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance
Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to the activation of multiple signaling pathways that are potential targets for disrupting the obesity–breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo. Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC ...
Source: Endocrine-Related Cancer - July 20, 2017 Category: Endocrinology Authors: Thiagarajan, P. S., Zheng, Q., Bhagrath, M., Mulkearns-Hubert, E. E., Myers, M. G., Lathia, J. D., Reizes, O. Tags: Research Source Type: research