Acetate dependence of tumors.

Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour's dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.

A Western-type diet accelerates tumor progression in an autochthonous mouse model of prostate cancer.

Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet--that is, enriched in both fat and cholesterol--accelerated prostate tumor incidence and tumor burden compared to mice fed a control chow diet. Furthermore, we also show that this diet increased the extent and the histological grade of prostate tumors. These findings were confirmed by the presence of increased levels of protein markers of advanced tumors in prostates obtained from animals fed a Western-type diet compared to those obtained from control animals. Increased lung metastases in animals fed a Western-type diet were also observed. In addition, we found that with a Western diet, animals bearing tumors presented with reduced plasma cholesterol levels compared with animals fed a control diet. Finally, we show that tumors obtained from animals fed a Western-type diet displayed increased expression of the high-density lipoprotein receptor SR-BI and increased angiogenesis. Taken together, our data suggest that dietary fat and cholesterol play an important role in the development of prostate cancer.

Malignant melanoma presenting as obstructive jaundice secondary to metastasis to the Ampulla of Vater.

CONTEXT: Malignant melanoma commonly metastasizes to the small intestine where it can cause pain, bleeding, and obstruction. However, jaundice from metastatic melanoma is relatively uncommon. CASE REPORT: A case of known malignant melanoma presenting as new onset obstructive jaundice as a result of a rarely reported metastasis to the ampulla of Vater. CONCLUSION: Multidisciplinary management of patients with metastatic melanoma is essential.

Extrapancreatic neural plexus invasion by pancreatic carcinoma: characteristics on magnetic resonance imaging.

BACKGROUND: Our objective is to study the characteristics of extrapancreatic neural plexus invasion by pancreatic carcinoma on MR imaging. METHODS: 20 patients with both pancreatic carcinoma and extrapancreatic neural plexus invasion confirmed by pathology were recruited in this study. MR imaging was performed within 1 month before surgery. On MR images, signal intensity at the site of potential extrapancreatic neural plexus invasion, lymph nodes and tumor size were noted. The relationship of extrapancreatic neural plexus invasion to these findings was analyzed. RESULTS: Signs of extrapancreatic neural plexus invasion were depicted on MR imaging in 80% of patients, which included streaky and strand-like signal intensity structure in fat tissue in 50% of patients and irregular masses adjacent to tumor in 30%. Signal intensity at invasion site was similar to that of pancreatic carcinoma. The frequencies of patients with vascular invasion and with lymph nodes larger than 5 mm were, respectively, 50% and 55%. Tumor diameter was 24 +/- 7 mm on MR imaging. Extrapancreatic neural plexus invasion was correlated with vascular invasion (r = 0.58, P < 0.005), slightly related with lymphadenopathy (r = 0.35, 0.1 > P > 0.05), but not related with tumor size. CONCLUSION: MR imaging is useful to depict extrapancreatic neural plexus invasion by pancreatic carcinoma.

Gallbladder abnormalities in carcinoma of pancreatic head: findings on MR imaging.

BACKGROUND: Our objective is to study the gallbladder abnormalities on MR images associated with carcinoma of the pancreatic head. METHODS: Thirty-six patients who had surgical resection of pancreatic head carcinoma were retrospectively analyzed regarding the appearance of the tumor and gallbladder on MR imaging performed within one month before surgery. The changes of the gallbladder wall, and the dimension of the gallbladder, cystic duct, pericholecystic region, and common bile duct (CBD) on MR imaging were noted. RESULTS: About 92% (33/36) of patients had at least one gallbladder abnormality on MR imaging, including thickened gallbladder wall (58%), gallbladder wall striation (19%), gallbladder wall severe enhancement (44%), enlarged gallbladder (33%), gallbladder stone (19%), dilatation of cystic duct (67%), focally increased liver parenchymal enhancement adjacent to the gallbladder (19%), and pericholecystic fluid (11%). 64% of patients had dilated CBD. The diameter of the cystic duct was correlated with those of the CBD (r = 0.45, P < 0.01) and gallbladder (r = 0.56, P < 0.0001). Enlarged gallbladder, dilatation of the cystic duct, and CBD were correlated with chronic cholecystitis. CONCLUSION: Most patients with pancreatic head carcinoma show gallbladder abnormalities on MR imaging. Cystic duct dilatation follows CBD dilatation and is the primary cause for dilated gallbladder and chronic cholecystitis in carcinoma of pancreatic head.

Malignant melanoma of the gallbladder: a report of two cases and review of the literature.

Melanoma metastatic to the gallbladder is rare. When present, it is often part of a widespread complex of metastases. Primary gallbladder melanomas are also extremely rare and can sometimes be difficult to distinguish from metastatic lesions. The optimal treatment for malignant melanoma of the gallbladder remains unclear, and prognosis is generally poor. We present here two cases of patients with metastatic lesions to the gallbladder. One patient presented with symptomatic cholelithiasis and was found incidentally to have a metastasis. Another patient had known a metastasis, but underwent curative resection of the only site of disease. We review the published literature for gallbladder melanoma, both primary and metastatic to determine the role of surgery in this disease.

Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling.

Vascular endothelial growth factor (VEGF) is a crucial pro-angiogenic component in pancreatic ductal adenocarcinoma (PDA), and its high expression levels have been correlated with poor prognosis and early postoperative recurrence. We have recently shown that high levels of angiotensin II (AngII) type 1 receptor (AT1R) correlate and colocalize with VEGF in invasive PDA and that AngII induces VEGF expression in PDA cell lines. In this study, we explored the signaling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1R and VEGF expression in noninvasive precursor lesions. An AT1R antagonist significantly (p<0.05) inhibited the AngII-mediated induction of VEGF messenger RNA and protein in all PDA cell lines. AngII-VEGF induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a mitogen-activated protein kinase signaling mechanism. AngII activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced VEGF synthesis. Immunohistochemical analysis of precursor lesions showed increased expression of AT1R in most ductal cells undergoing metaplasia. Pancreatic intraepithelial neoplasms showed more intense AT1R staining when compared to intraductal papillary mucinous neoplasms, which showed heterogeneous immunoreactivity. VEGF followed the same distribution pattern of AT1R in both lesions. AT1R expression in the premalignant pancreatic lesions suggests its involvement in tumor progression and angiogenesis. Our mechanistic findings provide the first insight into an AngII-initiated signaling pathway that regulates PDA angiogenesis. An AT1R-mediated VEGF induction suggests the possibility of AT1R blockade as a novel therapeutic strategy to control angiogenesis in PDA.

Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer.

PURPOSE: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

Gangliocytic paraganglioma: case report and review of the literature.

Gangliocytic paraganglioma is a rare tumor, which occurs nearly exclusively in the second portion of the duodenum. Generally, this tumor has a benign clinical course, although rarely, it may recur or metastasize to regional lymph nodes. Only one case with distant metastasis has been reported. We present a case of duodenal gangliocytic paraganglioma treated first by local resection followed by pylorus-preserving pancreaticoduodenectomy. Examination of the first specimen revealed focal nuclear pleomorphism and mitotic activity, in addition to the presence of three characteristic histologic components: epithelioid, ganglion, and spindle cell. In the subsequent pancreaticoduodenectomy specimen, there was no residual tumor identified in the periampullary area, but metastatic gangliocytic paraganglioma was present in two of seven lymph nodes. This case report confirms the malignant potential of this tumor. We review the published literature on gangliocytic paragangliomas pursuing a malignant course. We conclude that surgical therapy of these neoplasms should not be limited to local resection, as disease recurrence, lymph node involvement, and rarely distant metastasis may occur.

Metastatic melanoma causing jejunal intussusception.

The gastrointestinal (GI) tract is a common site of melanoma metastases although reports of small bowel intussusception are relatively rare. Most patients with intussusception will be symptomatic and resection will provide significant palliation. In rare instances, patients will have solitary metastases to the small intestine, and resection can provide long-term palliation and chance for cure. We describe a case of a patient with a widely metastatic melanoma who presented with crampy abdominal pain and CT findings of small bowel metastases. Exploration revealed jejunojejunal intussusception and resection provided excellent palliation.

Signal transducer and activator of transcription-3 and breast cancer prognosis.

Signal transducer and activator of transcription-3 (Stat3) is frequently activated in breast cancer and multiple lines of evidence suggest that Stat3 promotes tumor progression. However, the prognostic value of Stat3 in human breast cancer remains controversial and associations range from favorable to unfavorable based on four outcome studies of 62, 102, 255 and 517 patients. Cellular Stat3 protein expression was measured in three studies whereas nuclear localized, tyrosine phosphorylated Stat3 (Nuc-pYStat3) was used as the readout in only one study. We therefore retrospectively analyzed the prognostic value of Nuc-pYStat3 in a larger material of 721 breast cancer specimens. Overall, patients whose tumors were positive for Nuc-pYStat3 tended to have improved survival, but the trend did not reach statistical significance (P=0.08). When specimens were stratified by tumor grade, patients with low grade but not high grade tumors that were positive for Nuc-pYStat3 had significantly prolonged overall survival in univariate analysis (P=0.014) but not in multivariate analyses. Unexpectedly, quantitative immunofluoresence detection revealed highest levels of Nuc-pYStat3 in normal breast epithelia and gradual loss of Nuc-pYStat3 during progression from DCIS, invasive ductal carcinoma, and lymph node metastases. Levels of Nuc-pYStat3 correlated positively with levels of Nuc-pYStat5, a favorable prognostic marker, in invasive ductal carcinomas. Furthermore, NucpYStat3 levels correlated strongly with protein levels of nuclear localized Stat5a (r=0.633, P<0.001) but not Stat5b. Our data does not support the notion that Nuc-pYStat3 is an independent marker of prognosis in breast cancer, although future studies may reveal prognostic utility within molecularly characterized subtypes of breast cancer.

One year survival with poorly differentiated metastatic pancreatic carcinoma following chemoembolization with gemcitabine and cisplatin.

While hepatic arterial chemoembolization is efficacious for a number of malignancies, there is scant data regarding treatment of pancreatic adenocarcinoma. We report a complete radiographic response at one year from diagnosis of metastatic pancreatic carcinoma. Gemcitabine/cisplatin based chemoembolization may be of potential benefit for patients with liver-dominant metastases from pancreatic carcinoma. Given the typical survival of 6 months or less in this patient group with standard therapies, further research is warranted.

RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response.

In breast cancer, inactivation of the RB tumor suppressor gene is believed to occur via multiple mechanisms to facilitate tumorigenesis. However, the prognostic and predictive value of RB status in disease-specific clinical outcomes has remained uncertain. We investigated RB pathway deregulation in the context of both ER-positive and ER-negative disease using combined microarray datasets encompassing over 900 breast cancer patient samples. Disease-specific characteristics of RB pathway deregulation were investigated in this dataset by evaluating correlation among pathway genes as well as differential expression across patient tumor populations defined by ER status. Survival analysis among these breast cancer samples demonstrates that the RB-loss signature is associated with poor disease outcome within several independent cohorts. Within the ER-negative subpopulation, the RB-loss signature is associated with improved response to chemotherapy and longer relapse-free survival. Additionally, while individual genes in the RB target signature closely reproduce its prognostic value, they also serve to predict and monitor response to therapeutic compounds, such as the cytostatic agent PD-0332991. These results indicate that the RB-loss signature expression is associated with poor outcome in breast cancer, but predicts improved response to chemotherapy based on data in ER-negative populations. While the RB-loss signature, as a whole, demonstrates prognostic and predictive utility, a small subset of markers could be sufficient to stratify patients based on RB function and inform the selection of appropriate therapeutic regimens.

MR imaging for predicting the recurrence of pancreatic carcinoma after surgical resection.

OBJECTIVE: To study the relationship of characteristics of pancreatic carcinoma on MR imaging to tumor recurrence time after surgical resection. MATERIALS AND METHODS: Twenty-seven patients with pancreatic carcinoma were followed up at least 2 years after surgical resection of the tumor. All patients had MR imaging within 1 month before surgery. The tumor's size, signal intensity, local and vascular invasion, abdominal lymphadenopathy on MR imaging and the positive surgical margin were noted. The results from MR imaging were compared with the duration after surgery until tumor recurrence and with the positive surgical margin. RESULTS: 59% of patients had various degree of extrapancreatic invasion. The tumor recurrence times were, respectively, 24+/-21 months and 26+/-29 months in patients with and without vascular invasion (P=0.79). The combination of vascular with local invasion showed a correlation to the time of tumor recurrence (r=-0.34; P<0.05). Patients with positive surgical margins had a higher local invasion score on MR imaging and a shorter recurrence time than those with negative surgical margins. The number and size of lymph nodes were not related with tumor recurrence time. CONCLUSION: MR imaging was useful for predicting the recurrence of pancreatic carcinoma after surgical resection. Local invasion associated with and without vascular invasion on MR imaging was the indicator for the tumor recurrence.

Induction of monocyte chemoattractant protein-1 by nicotine in pancreatic ductal adenocarcinoma cells: role of osteopontin.

BACKGROUND: Cigarette smoke and nicotine are among the leading environmental risk factors for developing pancreatic ductal adenocarcinoma (PDA). We showed recently that nicotine induces osteopontin (OPN), a protein that plays critical roles in inflammation and tumor metastasis. We identified an OPN isoform, OPNc, that is selectively inducible by nicotine and highly expressed in PDA tissue from smokers. In this study, we explored the potential proinflammatory role of nicotine in PDA through studying its effect on the expression of monocyte chemoattractant protein (MCP)-1 and evaluated the role of OPN in mediating these effects. METHODS: MCP-1 mRNA and protein in PDA cells treated with or without nicotine (3-300 nmol/L) or OPN (0.15-15 nmol/L) were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Luciferase-labeled promoter studies evaluated the effects of nicotine and OPN on MCP-1 transcription. Intracellular and tissue colocalization of OPN and MCP-1 were examined by immunofluorescence and immunohistochemistry. RESULTS: Nicotine treatment significantly increased MCP-1 expression in PDA cells. Interestingly, blocking OPN with siRNA or OPN antibody abolished these effects. Transient transfection of the OPNc gene in PDA cells or their treatment with recombinant OPN protein significantly (P < .05) increased MCP-1 mRNA and protein and induced its promoter activity. MCP-1 was found in 60% of invasive PDA lesions, of whom 66% were smokers. MCP-1 colocalized with OPN in PDA cells and in the malignant ducts, and correlated well with higher expression levels of OPN in the tissue from patients with invasive PDA. CONCLUSION: Our data suggest that cigarette smoking and nicotine may contribute to PDA inflammation by inducing MCP-1 and provide a novel insight into a unique role for OPN in mediating these effects.

Involvement of osteopontin in the matrix-degrading and proangiogenic changes mediated by nicotine in pancreatic cancer cells.

BACKGROUND: Substantial evidence indicates that exposure to cigarette smoke is associated with an elevated risk of pancreatic ductal adenocarcinoma (PDA). However, the mechanisms underlying the effects of nicotine on the development or progression of PDA remain to be investigated. Previously, we showed that nicotine promotes the expression of osteopontin c (OPNc), an isoform of OPN protein that confers on cancer cells a migratory phenotype. In this study, we explored the potential prometastatic role of nicotine in PDA through studying its effect on the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) and evaluated the role of OPN in mediating these effects. MATERIALS AND METHODS: MMP-9 and VEGF mRNA and protein were analyzed in PDA cells treated with or without nicotine (3-300 nM). Transient transfection and luciferase-labeled promoter studies evaluated the effects of OPNc and OPN protein on the transcription and translation of MMP-9 and VEGF. Real-time PCR and immunohistochemistry were used to analyze the mRNA expression levels and localization of OPN, MMP-9, and VEGF proteins in matched invasive human PDA and surrounding nonmalignant tissues. RESULTS AND DISCUSSION: Nicotine significantly enhanced the expression of MMP-9 and VEGF mRNA and protein in PDA cells. Blocking OPN with siRNA or OPN antibody prevented the nicotine-mediated increase of both MMP-9 and VEGF. Transient transfection of OPNc gene in PDA cells or their treatment with recombinant OPN protein significantly (p < 0.05) increased MMP-9 and VEGF mRNA expression levels and induced their promoter activities. In invasive PDA lesions, MMP-9 mRNA levels were significantly (p < 0.005) higher in smokers vs. nonsmokers. VEGF protein co-localized with MMP-9 and OPN in the malignant ducts and correlated well with their higher levels in invasive PDA lesions. CONCLUSIONS: Our data show for the first time that cigarette smoking and nicotine may contribute to PDA metastasis through inducing MMP-9 and VEGF and suggest that OPN plays a central role in mediating these effects. The presence of OPN as a downstream effector of nicotine that is capable of mediating its prometastatic effects in PDA cells is novel and could provide a unique therapeutic target to control pancreatic cancer aggressiveness, especially in the cigarette-smoking population.

Identifying pancreatic cancer patients for targeted treatment: the challenges and limitations of the current selection process and vision for the future.

Recent preclinical data have demonstrated that pancreatic adenocarcinoma (PDA) cells with defects in the Fanconi anemia/BRCA2 pathway are hypersensitive to interstrand crosslinking agents. The challenge is to efficiently identify patients who will benefit from these therapies. Patients were chosen for this study by evaluating personal history, ethnic background and family history of pancreatic malignancy. Molecular assays were performed on tissue samples. Patient A developed PDA in the context of a known BRCA2 frameshift mutation (2157delG), suspected because of her personal and multigenerational family history of breast cancer. She was treated with surgical resection, and targeted chemotherapy. Patient A continues to be disease free 32 months after her diagnosis and treatment. Patient B developed PDA in the context of a strong family history of PDA and Ashkenazi Jewish heritage. Genetic analysis on critical DNA repair genes revealed no alterations. This patient did not receive a tailored treatment regimen. This study highlights the challenge of treating PDA patients and selecting those eligible for targeted therapy. The current targeted treatment options for PDA are reviewed. A new multidisciplinary approach for stratifying PDA patients for promising targeted adjuvant therapy and familial risk counseling is proposed.

The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth.

Initially isolated as the dominant suppressor of the mutant epidermal growth factor receptor (ellipse), the Dachshund gene plays a key role in metazoan development regulating the Retinal Determination Gene Network. Herein, the DACH1 gene was expressed in normal prostate epithelial cells with reduced expression in human prostate cancer. DACH1 inhibited prostate cancer cellular DNA synthesis, growth in colony forming assays, and blocked contact-independent growth in soft agar assays. DACH1 inhibited androgen receptor (AR) activity, requiring a conserved DS Domain (Dachshund domain conserved with Ski/Sno) that bound NCoR/HDAC and was recruited to an androgen-responsive gene promoter. DACH1 inhibited ligand-dependent activity of AR mutations identified in patients with androgen-insensitive prostate cancer. The DS domain was sufficient for repression of the AR wild-type but failed to repress an AR acetylation site point mutant. These studies show a role for the Retinal Determination Gene Network in regulating cellular growth and signaling in prostate cancer.