Pancreatic Cancer, Leptin, and Chemoresistance: Current Challenges

Pancreatic cancer (PC) remains a leading cause of cancer-related deaths. Currently, conventional chemotherapies have showed only limited benefits for PC patients. Main factors affecting PC treatment failures are due to late detection, lack of early symptoms and biomarkers, and the development of desmoplasia and chemoresistance. Various mechanisms have been implicated in PC chemoresistance that includes stem cells, epigenetic changes, and alteration of signaling pathways, among others. Obesity is a modifiable factor for PC risk, which is characterized by high levels of the adipokine leptin that is a proinflammatory, proangiogenic, survival factor that affects chemotherapy effectiveness. Here, we will discuss on the mechanisms of PC chemoresistance and the influence of obesity and leptin signaling. Furthermore, the potential use of nontoxic leptin antagonists as a novel sensitization strategy for PC chemotherapeutics will also be discussed

Endometrial carcinoma with ectopic human chorionic gonadotropin expression

• Aggressive course and treatment resistance characterize ectopic human chorionic gonadotropin. • Recurrence of endometrial cancer with ectopic hCG was treated with brachytherapy and EMACO. • The serum hCG level can serve as a marker in tumors with ectopic hCG expression

Emerging Biomarkers and Clinical Implications in Endometrial Carcinoma

Endometrial cancer (EmCa) is the most common type of gynecological cancer. EmCa is the fourth most common cancer in the United States, which has been linked to increased incidence of obesity. EmCa can be classified into two main types: Type I and Type II, which include the major histological subtypes. Type I EmCa is hormonally driven, less aggressive, and has a more favorable prognosis. In contrast, Type II EmCa grows independently of hormonal signals, is more aggressive, and generally has an unfavorable prognosis. Various tumor biomarkers [i.e., tumor suppressor p53, hypoxia-inducible factor 1-alpha (HIF1-α), human epidermal growth factor receptor 2 (HER2/neu), and vascular endothelial growth factor (VEGF)] have been identified in EmCa. Biomarkers of treatment effectiveness involve immunosuppressive factors targeted by microRNA (miRNA)-based therapy. However, there are no reliable biomarker tests for early detection of EmCa and treatment effectiveness. A potential new biomarker is Notch, Interleukin-1, leptin crosstalk outcome (NILCO) that could affect the progression of Type II EmCa. NILCO expression in EmCa might be dependent on patient’s obesity status. This chapter presents updated information on these, and other potential emerging biomarkers for EmCa, and discusses current challenges and clinical implications on this area of research

Chemotherapy Used to Halt Lower GI Bleeding in a Rare Case of Metastatic Choriocarcinoma to the GI Tract

Choriocarcinoma, a nonseminomatous germ cell tumor, is a rare type of testicular malignancy that tends to occur in young males. It is, however, exceedingly rare for choriocarcinoma to involve the GI tract. In this article, we present a rare case of a 31-year-old male, diagnosed with choriocarcinoma of the left testes, along with several metastases to distant sites. The patient presented with headaches and severe lower GI bleeding due to metastases to the GI tract, which was eventually controlled with systemic chemotherapy, while requiring several units of packed RBCs during his admission to the hospital. An extensive literature review found very few cases of the occurrence of GI bleeding as a consequence of choriocarcinoma due to metastases to the GI tract

Novel Role for the Golgi Membrane Protein TMEM165 in Control of Migration and Invasion for Breast Carcinoma

The TMEM165 gene encodes for a multiple pass membrane protein localized in the Golgi that has been linked to congenital disorders of glycosylation. The TMEM165 protein is a putative ion transporter that regulates H+/Ca++/Mn++ homeostasis and pH in the Golgi. Previously, we identified TMEM165 as a potential biomarker for breast carcinoma in a glycoproteomic study using late stage invasive ductal carcinoma tissues with patient-matched adjacent normal tissues. The TMEM165 protein was not detected in non-malignant matched breast tissues and was detected in invasive ductal breast carcinoma tissues by mass spectrometry. Our hypothesis is that the TMEM165 protein confers a growth advantage to breast cancer. In this preliminary study we have investigated the expression of TMEM165 in earlier stage invasive ductal carcinoma and ductal carcinoma in situ cases. We created a CRISPR/Cas9 knockout of TMEM165 in the human invasive breast cancer cell line MDAMB231. Our results indicate that removal of TMEM165 in these cells results in a significant reduction of cell migration, tumor growth, and tumor vascularization in vivo. Furthermore, we find that TMEM165 expression alters the glycosylation of breast cancer cells and these changes promote the invasion and growth of breast cancer by altering the expression levels of key glycoproteins involved in regulation of the epithelial to mesenchymal transition such as E-cadherin. These studies illustrate new potential functions for this Golgi membrane protein in the control of breast cancer growth and invasion

Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study

Background: Androgen Receptor (AR) has emerged as a potential therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, conflicting reports regarding AR’s prognostic role in TNBC are putting its usefulness in question. Some studies conclude that AR positivity indicates a good prognosis in TNBC whereas others suggest the opposite, and some show that AR status has no significant bearing on the patients’ prognosis. Methods: We evaluated the prognostic value of AR in resected primary tumors from TNBC patients from six international cohorts {US (n=420), UK (n=239), Norway (n=104), Ireland (n=222), Nigeria (n=180), and India (n=242); total n=1407}. All TNBC samples were stained with the same anti-AR antibody using the same immunohistochemistry protocol, and samples with ≥1% of AR-positive nuclei were deemed AR-positive TNBCs. Results: AR status shows population-specific patterns of association with patients’ overall survival after controlling for age, grade, population, and chemotherapy. We found AR-positive status to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norway, Ireland and Indian cohorts, and neutral in UK cohort. Conclusion: AR status, on its own, is not a reliable prognostic marker. More research to investigate molecular subtype composition among the different cohorts is warranted

Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer

Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance

The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer

There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years

Chemotherapy Used to Halt Lower GI Bleeding in a Rare Case of Metastatic Choriocarcinoma to the GI Tract

Choriocarcinoma, a nonseminomatous germ cell tumor, is a rare type of testicular malignancy that tends to occur in young males. It is, however, exceedingly rare for choriocarcinoma to involve the GI tract. In this article, we present a rare case of a 31-yearold male, diagnosed with choriocarcinoma of the left testes, along with several metastases to distant sites. The patient presented with headaches and severe lower GI bleeding due to metastases to the GI tract, which was eventually controlled with systemic chemotherapy, while requiring several units of packed RBCs during his admission to the hospital. An extensive literature review found very few cases of the occurrence of GI bleeding as a consequence of choriocarcinoma due to metastases to the GI tract

IRAK4 and TLR3 sequence variants may alter breast cancer risk among African-American women

Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68-4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK-4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK-4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK-4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK-4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK-4 and its XCT in cell transformation and innate immunity