Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case–control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27–3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III–IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.
Roberto Valente, Alastair J Hayes, Sven-Petter Haugvik, Per Hedenström, Darko Siuka, Emilie Korsæth, Daniel Kämmerer, Stuart M Robinson, Patrick Maisonneuve, Gianfranco Delle Fave, Bjorn Lindkvist and Gabriele Capurso
Carly Jade Dool, Haider Mashhedi, Mahvash Zakikhani, Stéphanie David, Yunhua Zhao, Elena Birman, Joan M Carboni, Marco Gottardis, Marie-José Blouin and Michael Pollak
Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.
Emma H Allott and Stephen D Hursting
Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link.
YunFeng Cui and Dana K Andersen
Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage.
J Lado-Abeal, R Celestino, S B Bravo, M E R Garcia-Rendueles, J de la Calzada, I Castro, P Castro, C Espadinha, F Palos, P Soares, C V Alvarez, M Sobrinho-Simões and J Cameselle-Teijeiro
Our main objective was to search for mutations in candidate genes and for paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement in a well-differentiated angioinvasive follicular thyroid carcinoma (FTC) causing hyperthyroidism. DNA and RNA were extracted from the patient's thyroid tumor, as well as ‘normal’ thyroid tissue, and from peripheral blood lymphocytes (PBLs) of the patient, her daughter, and two siblings. Nuclear isolation was extracted from the patient's tumor, ’normal’ thyroid tissue, PBLs, and uterine leiomyoma tissue. TSH receptor (TSHR), RAS, and BRAF genes were sequenced. We searched for PAX8 – PPAR γ in thyroid, PBL, and uterine leiomyoma samples from the patient and family members. Proliferative effects of detected mutants on non-transformed human thyrocytes cultures. An activating TSHR mutation, M453T, was detected in the tumor. PAX8 (exons 1 – 8 + 10)– PPAR γ was found in all tested patient's tissues. A second rearrangement, PAX8 (exons 1 – 8)– PPAR γ, was detected in the patient's normal thyroid tissue. Under deprived medium condition, co-transfection of PAX8 – PPAR γ and TSHR – M453T dramatically increased the number of thyrocytes, an effect that it was not observed with TSHR wild-type (WT); under complete medium conditions, co-transfection of PAX8 – PPAR γ with either TSHR – M453T or TSHR – WT inhibited cell proliferation. We report a patient with hyperthyroidism due to a FTC bearing an activating TSHR mutation and PAX8 – PPAR γ rearrangements. PAX8 – PPAR γ was present as a mosaicism affecting tissues from endodermal and mesodermal origin. PAX8 – PPAR γ and TSHR – M453T inhibited or promoted thyrocyte proliferation depending on medium conditions. The activating TSHR mutation could promote in vivo FTC development in PAX8 – PPAR γ-positive thyrocytes under poor blood supply with deprivation of growth factors but restraint the tumor growth when growth factors are supplied.
Hong-Jun Song, Yan-Li Xue, Yan-Hong Xu, Zhong-Ling Qiu and Quan-Yong Luo
Differentiated thyroid cancer (DTC) is usually indolent with good prognosis and long-term survival. However, DTC distant metastasis is often a grave event and accounts for most of its disease-specific mortality. The major sites of distant metastases are the lung and bone. Metastases to the brain, breast, liver, kidney, muscle, and skin are rare or relatively rare. Nevertheless, recognizing rare metastases from DTC has a significant impact on the clinical decision making and prognosis of patients. 131I single photon emission computed tomography/computed tomography (131I-SPECT/CT) can provide both metabolic and anatomic information about a lesion; therefore, it can better localize and define the 131I-WBS findings in DTC patients. In this pictorial review, the imaging features of a range of rare metastases from DTC are demonstrated, with a particular emphasis on the 131I-SPECT/CT diagnostic aspect.
Hao Fu, Lin Cheng, Yuchen Jin and Libo Chen
Thyrotoxicosis with concomitant thyroid cancer is rare and poorly recognized, which may result in delayed diagnosis, inappropriate treatment and even poor prognosis. To provide a comprehensive guidance for clinicians, the etiology, pathogenesis, diagnosis and treatment of this challenging setting were systematically reviewed. According to literatures available, the etiologies of thyrotoxicosis with concomitant thyroid cancer were categorized into Graves’ disease with concurrent differentiated thyroid cancer (DTC) or medullary thyroid cancer, Marine–Lenhart Syndrome with coexisting DTC, Plummer’s disease with concomitant DTC, amiodarone-induced thyrotoxicosis with concomitant DTC, central hyperthyroidism with coexisting DTC, hyperfunctioning metastases of DTC and others. The underlying causal mechanisms linking thyrotoxicosis and thyroid cancer were elucidated. Medical history, biochemical assessments, radioiodine uptake, anatomic and metabolic imaging and ultrasonography-guided fine-needle aspiration combined with pathological examinations were found to be critical for precise diagnosis. Surgery remains a mainstay in both tumor elimination and control of thyrotoxicosis, while anti-thyroid drugs, beta-blockers, 131I, glucocorticoids, plasmapheresis, somatostatin analogs, dopamine agonists, radiation therapy, chemotherapy and tyrosine kinase inhibitors should also be appropriately utilized as needed.
Christopher W Rowe, Jonathan W Paul, Craig Gedye, Jorge M Tolosa, Cino Bendinelli, Shaun McGrath and Roger Smith
Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.
Hyun-Seuk Moon and Christos S Mantzoros
Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1β (IL1β) in cancer pathogenesis. Direct evidence that IL1β contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1β may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1β-regulated malignant potential in human and mouse colon cancer cell lines. IL1β increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1β-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1β in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1β-induced colon carcinogenesis.
According to the literature thyroid nodules are quite rare in the first two decades of life. However, there are some exceptions, relating to areas with an iodine deficiency or affected by radioactive fallout, where the risk of nodules and carcinomas is increased. Therefore, it is a great challenge for the physician to distinguish between benign and malignant lesions preoperatively, and not only in these areas of greater risk. A careful work-up, comprising the patient’s history, clinical examination, laboratory tests, thyroid ultrasound, scintigraphy, fine-needle aspiration biopsy (FNAB) and molecular studies, is mandatory to improve the preoperative diagnosis. The differential diagnosis should also include benign thyroid conditions such as: (i) congenital hypothyroidism due to dyshormonogenesis or ectopy, (ii) thyroid hemiagenesis, (iii) thyroglossal duct cyst, (iv) simple goiter, (v) cystic lesion, (vi) nodular hyperplasia, (vii) follicular adenoma, (viii) Graves’ disease and (ix) Hashimoto thyroiditis, all of which can predispose to the development of thyroid nodules. The majority of thyroid carcinomas derive from the follicular cell (papillary, follicular, insular and undifferentiated (or anaplastic) thyroid carcinoma), whereas medullary thyroid carcinoma derives from calcitonin-producing cells. Inherited forms of thyroid cancer may occur, especially in relation to medullary thyroid carcinoma. FNAB is a critical factor in establishing the preoperative diagnosis. However, we should keep in mind the fact that a conventional cytological evaluation can miss the neoplastic nature of a lesion and the employment of immunocytochemical and molecular studies of aspirates from FNAB can give us a more precise diagnosis of neoplasia in thyroid nodules once they are detected.