Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.

p21 Protein Outperforms Clinico-pathological Criteria in Predicting Liver Metastases in Pancreatic Endocrine Tumors.

BACKGROUND/AIM: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases. MATERIALS AND METHODS: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases. RESULTS: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values. CONCLUSION: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.

Survivin Dendritic Cell Vaccine Safely Induces Immune Responses and Is Associated with Durable Disease Control after Autologous Transplant in Patients with Myeloma.

PURPOSE: We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma. PATIENTS AND METHODS: This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified. RESULTS: A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41-88). CONCLUSIONS: Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach. See related commentary by Dhodapkar, p. 4524.

An miRNA Signature Predicts Grading of Pancreatic Neuroendocrine Neoplasms.

BACKGROUND/AIM: Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. PATIENTS AND METHODS: Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. RESULTS: There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. CONCLUSION: The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.

Incidental Gastric Langerhans Cell Histiocytosis and Synchronous Adenocarcinoma of the Colon: An Interesting Case Report and Literature Review.

BACKGROUND/AIM: Langerhans cell histiocytosis (LCH) is an uncommon disorder characterized by an abnormal monoclonal proliferation of pathologic Langerhans cells. The clinical presentation of LCH is very unpredictable, ranging from single-system limited disease to severe multi-organ disease with a high mortality rate. LCH usually affects children and very rarely adults. The most common body parts affected by LCH are the bones, skin, lungs, pituitary glands, and lymph nodes. Gastrointestinal tract involvement by LCH is exceptionally rare, and only a few cases have been reported. CASE REPORT: We present the case of a 50-year-old woman who was referred to our clinic by her primary care physician for an upper endoscopy and colonoscopy and was diagnosed with H. pylori-related gastritis and a synchronous gastric LCH and primary colonic adenocarcinoma. We describe the histologic characteristics and clinical implications of the LCH diagnosis. A review of the published literature revealed that LCH presenting as a gastric solitary lesion is rare. CONCLUSION: This case highlights the importance of recognizing this rare condition to ensure proper patient follow-up.

Sebaceous Gland Ectopia of the Esophagus: A Challenging Clinical Diagnosis.

BACKGROUND/AIM: Sebaceous gland ectopia (SGE) defines the presence of normal sebaceous tissue in an unusual location. This condition is rare and was first described in ectodermal-derived organs, such as the oral cavities and palms, and later in endodermal-derived tissues including the esophagus. SGE of the esophagus is believed to represent a form of acquired metaplasia. SGE is asymptomatic and usually discovered during routine endoscopic examinations for other gastrointestinal complaints and symptoms. It is a benign entity and to date no cases of malignant transformation have been reported. Once diagnosed, SGE requires no further work up or follow up, and does not require treatment. CASE REPORT: We present two cases of SGE arising in the esophagi of two female patients who presented with complaints of gastro-esophageal reflux and underwent endoscopy. These lesions presented as patchy yellow-white nodules in the mid and upper esophagus and were endoscopically interpreted as suggestive of candidiasis or glycogen acanthosis. Biopsies showed foci of non-keratinizing squamous mucosa overlying the sebaceous glands. These glands exhibited a characteristic lobulated structure with germinative cells at the periphery and vacuolated, well-differentiated cells in the center of the lobules. After histologic examination, the endoscopic impressions of candidiasis and acanthosis were ruled out and the final diagnosis of SGE was made. There was no evidence of dysplasia or malignancy in our cases. CONCLUSION: Histopathology examination is important to differentiate SGE from malignant and infectious conditions that are more common, and which can be clinically and endoscopically similar to SGE.

A Novel PHD2/VHL-mediated Regulation of YAP1 Contributes to VEGF Expression and Angiogenesis.

The transcriptional co-activator YAP1 is the major oncogenic component of the Hippo signaling pathway and contributes to the genesis and progression of various tumors, including non-small cell lung cancer (NSCLC). YAP1 levels are regulated by the canonical Hippo kinases, MST1/2 and LATS1/2, which modulate its cytoplasmic retention and proteasomal degradation. While non-canonical regulation of YAP1 has been reported, its role in hypoxic response is not fully elucidated. The studies presented here show that YAP1 levels and function are modulated by VHL and PHD2. YAP1 could regulate multiple genes involved in angiogenesis through E2F1; it also associates with HIF1α in cancer cells under hypoxic conditions, inducing the VEGF-A promoter. Under normoxic conditions, PHD2 associates with and hydroxylates specific proline residues on YAP1, facilitating its interaction with VHL and promoting ubiquitination and subsequent proteasomal degradation. Exposure to hypoxia dissociates YAP1 from PHD2 and VHL, elevating YAP1 levels and enhancing its association with HIF1α. YAP1-HIF1α interaction was higher in NSCLC and RCC samples, indicating a role for this interaction in the genesis of these cancers. Our results thus reveal a novel mode of regulation of YAP1 by PHD2 and VHL in normoxic cells, suggesting that YAP1-mediated induction of VEGF and other genes contributes to hypoxic response in tumors.

Chemical complementarity between tumor resident, T-cell receptor CDR3s and MAGEA3/6 correlates with increased melanoma survival: Potential relevance to MAGE vaccine auto-reactivity.

Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.

An Analysis of the Impact of COVID-19 Pandemic-related Lockdown Measures on a Large Gastrointestinal Pathology Service in the United States.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) pandemic prompted global recommendations to delay non-urgent endoscopic procedures to limit the spread of SARS-COV-2, but such delays had unprecedented impact on the delivery of healthcare. Being a large specialty GI Pathology service, we sought to analyze the effect of the pandemic on the frequency of GI malignancies in our department. PATIENTS AND METHODS: Based on the electronic search of departmental pathology records, we compared the total numbers of cancer diagnoses (primary and metastatic) from various GI biopsy sites during the 12-month pre- and post-pandemic periods. We summarized patient demographics and analyzed pertinent histopathologic data. RESULTS: For all GI biopsy sites, the number of intramucosal/invasive malignancies reported during the one-year pre-COVID-19 pandemic (pre-COVID) and post-COVID-19 pandemic national lockdown (post-COVID) observation periods were 146 and 218, respectively. Among these, 32 and 70 malignancies were reported for the first quarter (representing the earliest post-lockdown period), 29 and 53 for the second, 41 and 54 for the third, and 44 and 41 for the fourth quarter. During the first two quarters of the post-COVID observation period, the increase in malignant diagnoses was most profound, showing 119% post-COVID increase compared to the pre-COVID levels. Of the two main primary histologic types of large intestinal carcinomas [adenocarcinoma (ADC) and squamous cell carcinoma (SCC)], the most profound post-COVID increase was noted in SCCs (136% vs. 58% for ADCs). CONCLUSION: Compared to the pre-pandemic baseline, the COVID-19 pandemic caused a major increase in biopsy diagnoses of GI cancers in our department. The most plausible explanations for this trend include inevitable lockdowns to minimize the spread of SAR-COV2, which affected GI endoscopy procedure schedules/re-schedules as well as patient response and adaptation to emerging post-COVID GI healthcare patterns. The COVID-19 pandemic's long-term impact on the health of GI cancer patients will need to be determined through systematic analyses by multi-disciplinary teams.

Anticancer function of microRNA-30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer.

Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration-resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR-30e through the regulation of genes involved in various signaling pathways. We noted loss of miR-30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR-30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR-30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR-30e and its RNA targets. We noted a newly identified reciprocal relationship between miR-30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR-30e. Transcriptome profiling and quantitative real-time PCR (qRT-PCR) validation of miR-30e-expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR-30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa.

Expression of DNA Mismatch Repair Proteins, PD1 and PDL1 in Barrett's Neoplasia.

BACKGROUND/AIM: Cancers with a microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status respond to immune checkpoint inhibition (ICI). Regardless of the tumor type, MSI-H/dMMR status is a reliable biomarker for ICI responsiveness. This study aimed at determining the MSI-H status in precursor lesions to esophageal adenocarcinoma (EAC) such as Barrett's esophagus (BE) and BE with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). PATIENTS AND METHODS: We performed immunohistochemical staining (IHC) for PMS2, MSH6, PD1, and PD-L1. RESULTS: All cases of BE (50), LGD (48), and HGD (50) had intact PMS2 and MSH6 nuclear expression; were negative for PD1; and had a PD-L1 combined positive score (CPS) score <1. One EAC case (2%) was negative for PMS2 nuclear expression. One HGD case (2%) and two EAC cases (4%) were PD1 positive (CPS score <1 applied to PD1). One EAC case (2%) had a CPS score >1, and one EAC case (2%) was MSI-H. MSI-H tumors usually show PD-L1 expression, although the MSI-H EAC in this study had a PD-L1 CPS score of <1. CONCLUSION: Further studies investigating EAC and its precursor lesions for PD1, PD-L1, and dMMR status may be informative regarding the immunogenicity of the evolution of EAC.

Benefit of Gene Expression Profiling in Gastrointestinal Neuroendocrine Tumors of Unknown Primary Origin.

BACKGROUND/AIM: Cancer of unknown primary (CUP), representing 3-5% of all newly diagnosed cancers in the United States, is a presumptive, non-definitive diagnosis rendered when a primary tumor site cannot be identified after exhaustive diagnostic evaluation, including cases of neuroendocrine neoplasms (NENs). CUPs are characterized by findings that are challenging to reconcile, including inconclusive immunohistochemical (IHC) stains, an undifferentiated morphologic phenotype, history of multiple cancers, a clinical presentation that is discordant from histologic findings, an atypical distribution of metastases, or lack of expected response to treatment. For a significant subset of NENs (10%), traditional diagnostic evaluation is unable to determine a primary tumor site using histomorphology and IHC stains. Gene expression profiling (GEP) of either mRNA or microRNA is the technique utilized in the three commercially available platforms that provide a prediction of tumor type in cases of diagnostic uncertainty of CUPs, including those with neuroendocrine differentiation. Case Series Report: Here we present four cases of NENs, where the diagnosis based upon histomorphological and IHC features presented a unique challenge that ultimately benefited from the integration of molecular tumor classification using the validated assay. CancerTYPE ID by Biotheranostics is based on a quantitative RT-PCR assay that uses a computational algorithm to measure the collective expression of 92 genes (87 cancer-related genes and 5 control genes). This case series reports five appropriate clinical scenarios that highlight the utility of a GEP-based assay to effectively provide a molecular tumor classification to identify NEN subtypes and tumor primary site of origin. CONCLUSION: These cases demonstrated that the CancerTYPE ID test was able to resolve challenging diagnoses for primary and metastatic NENs. These cases emphasize the clinical need of utilizing a GEP-based assay for determining the anatomic site of origin and NEN subtyping, both essential for the appropriate clinical management of NENs.

A microRNA Signature Identifies Patients at Risk of Barrett Esophagus Progression to Dysplasia and Cancer.

BACKGROUND: Progression of Barrett esophagus (BE) to esophageal adenocarcinoma occurs among a minority of BE patients. To date, BE behavior cannot be predicted on the basis of histologic features. AIMS: We compared BE samples that did not develop dysplasia or carcinoma upon follow-up of ≥ 7 years (BE nonprogressed [BEN]) with BE samples that developed carcinoma upon follow-up of 3 to 4 years (BE progressed [BEP]). METHODS: The NanoString nCounter miRNA assay was used to profile 24 biopsy samples of BE, including 13 BENs and 11 BEPs. Fifteen samples were randomly selected for miRNA prediction model training; nine were randomly selected for miRNA validation. RESULTS: Unpaired t tests with Welch's correction were performed on 800 measured miRNAs to identify the most differentially expressed miRNAs for cases of BEN and BEP. The top 12 miRNAs (P < .003) were selected for principal component analyses: miR-1278, miR-1301, miR-1304-5p, miR-517b-3p, miR-584-5p, miR-599, miR-103a-3p, miR-1197, miR-1256, miR-509-3-5p, miR-544b, miR-802. The 12-miRNA signature was first self-validated on the training dataset, resulting in 7 out of the 7 BEP samples being classified as BEP (100% sensitivity) and 7 out of the 8 BEN samples being classified as BEN (87.5% specificity). Upon validation, 4 out of the 4 BEP samples were classified as BEP (100% sensitivity) and 4 out of the 5 BEN samples were classified as BEN (80% specificity). Twenty-four samples were evaluated, and 22 cases were correctly classified. Overall accuracy was 91.67%. CONCLUSION: Using miRNA profiling, we have identified a 12-miRNA signature able to reliably differentiate cases of BEN from BEP.

Ethylmalonic Encephalopathy 1 Protein Is Increased in Colorectal Adenocarcinoma.

BACKGROUND/AIM: Ethylmalonic encephalopathy 1 protein (ETHE1) plays an important role in sulfide catabolism and polysulfide formation. As sulfides and polysulfides have recently been identified as playing important roles in cancer, we hypothesized that ETHE1 expression would be increased in colon cancer. MATERIALS AND METHODS: We used tissue microarray analysis to compare ETHE1 expression in benign colonic epithelium compared to colonic adenocarcinoma. In total, 26 benign colonic epithelial samples were compared to 122 cases of colonic adenocarcinomas. RESULTS: Compared to benign colonic epithelium, ETHE1 expression was significantly increased (~two-fold) in colonic adenocarcinoma. Additionally, this expression increased with increasing colon cancer tumor grades. CONCLUSION: ETHE1 expression is increased in colon cancer compared to benign colonic epithelium. These data, combined with previous studies, suggest that ETHE1 may contribute to colon carcinogenesis by promoting tumor cell bioenergetics and polysulfide formation.

Cystathionine Gamma-Lyase Is Increased in Testicular Seminomas, Embryonal, and Yolk Sac Tumors.

BACKGROUND: Testicular cancer constitutes 1.0% of male cancer and typically carries a good prognosis. As far as we are aware, the role for hydrogen sulfide in testicular cancer and the level of hydrogen sulfide-synthesizing enzyme have never been addressed. Here we examined cystathionine gamma-lyase (CSE) expression in several germ-cell testicular tumors. MATERIALS AND METHODS: Tissue microarrays were employed to examine CSE expression in 32 benign testicular samples, 88 testicular seminomas, 34 embryonal carcinomas, 4 mature teratomas, and 16 yolk sac tumors, and CSE expression was compared to that seen in benign testicular tissue. RESULTS: Compared to benign testicular tissue, CSE expression was increased in all three types of testicular neoplasm but not in mature teratomas. Highest CSE expression was identified in embryonal carcinomas, which often show a relatively aggressive clinical course. CONCLUSION: For the first time, we show that CSE is increased in several common testicular germ-cell tumor types.

Clinical Characteristics and Outcomes of Colorectal Cancer in the ColoCare Study: Differences by Age of Onset.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III-IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82-3.83) and 2.00 (1.43-2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21-1.98) and 0.56 (0.41-0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

LncRNA PAINT is associated with aggressive prostate cancer and dysregulation of cancer hallmark genes.

Long noncoding RNAs (lncRNAs) play regulatory role in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a lncRNA PAINT (prostate cancer associated intergenic noncoding transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT was noted in advanced stage and metastatic PCa. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680. Inhibition of PAINT decreased cell migration and reduced expression of Slug and Vimentin. Ectopic expression of PAINT suppressed E-cadherin, increased S-phase progression and cell migration. PAINT expression in PCa cells induced larger colony formation, increased tumor growth and higher expression of mesenchymal markers. Transcriptome analysis followed by qRT-PCR validation showed differentially expressed genes involved in epithelial mesenchymal transition (EMT), apoptosis and drug resistance in PAINT-expressing cells. Our study establishes an oncogenic function of PAINT in PCa.

Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis.

The activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/ß-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and ß-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

Pancreatic-type Mixed Acinar-neuroendocrine Carcinoma of the Stomach: A Case Report and Literature Review.

Background: Pancreatic-type mixed acinar-neuroendocrine carcinoma (PMANEC) in the stomach is very rare. We report a case of PMANEC that was initially misdiagnosed as a gastric neuroendocrine tumor. Case Report: A 63-year-old female was found to have a gastric mass by histology and immunohistochemistry. The tumor had a heterogenous histology, with areas resembling pancreatic acinar cell carcinoma and other areas exhibiting neuroendocrine features. Only the neuroendocrine component was present in the initial biopsy, resulting in the erroneous diagnosis of gastric neuroendocrine tumor. Evaluation of the final resected tumor revealed cells expressing pancreatic exocrine markers, including trypsin and chymotrypsin and BCL10 immune signaling adaptor. Large areas of the tumor (>30%) were also positive for chromogranin A and synaptophysin. The final diagnosis was PMANEC. Conclusion: This type of gastric cancer is rare and may cause diagnostic difficulty, especially if only the neuroendocrine component of the tumor is sampled in a biopsy.

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2.

Non-small cell lung cancer (NSCLC) is known to have poor patient outcomes due to development of resistance to chemotherapy agents and the EGFR inhibitors, which results in recurrence of highly aggressive lung tumors. Even with recent success in immunotherapy using the checkpoint inhibitors, additional investigations are essential to identify novel therapeutic strategies for efficacious treatment for NSCLC. Our finding that high levels of histone deacetylase 11 (HDAC11) in human lung tumor tissues correlate with poor patient outcome and that depletion or inhibition of HDAC11 not only significantly reduces self-renewal of cancer stem cells (CSCs) from NSCLC but also decreases Sox2 expression that is essential for maintenance of CSCs, indicates that HDAC11 is a potential target to combat NSCLC. We find that HDAC11 suppresses Sox2 expression through the mediation of Gli1, the Hedgehog pathway transcription factor. In addition, we have used highly selective HDAC11 inhibitors that not only target stemness and adherence independent growth of lung cancer cells but these inhibitors could also efficiently ablate the growth of drug-insensitive stem-like cells as well as therapy resistant lung cancer cells. These inhibitors were found to be efficacious even in presence of cancer associated fibroblasts which have been shown to contribute in therapy resistance. Our study presents a novel role of HDAC11 in lung adenocarcinoma progression and the potential use of highly selective inhibitors of HDAC11 in combating lung cancers.