Latest Pancreatic Cancer Genomics Papers

Here are the latest additions to the Pancreatic Cancer Genomics group in Mendeley.  This week’s papers an entry on a potential diagnostic, and a couple of papers on BRCA2 mutations and how patients with those mutations may respond better to a therapeutic regimen that includes a cross-linked agent.  This week’s collection also includes some related papers from previous years.

  • Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy.
    Cancer research (2007). Volume: 67, Issue: 2. Pages: 433-6.Ajay P Singh, Pallavi Chaturvedi, Surinder K Batra et al.The MUC4 mucin is a transmembrane glycoprotein that is implicated in the pathogenesis of pancreatic cancer and is aberrantly expressed in many other epithelial carcinomas. Recent studies suggest its significant potential as a clinical tool for cancer diagnosis and prognosis. MUC4 modulates HER2/ErbB2 signaling and is a determinant of therapeutic outcome of Herceptin-based therapy, which further indicates its prospective usefulness in cancer therapy and treatment planning.
  • Novel INTeraction of MUC4 and galectin: potential pathobiological implications for metastasis in lethal pancreatic cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research (2011). Volume: 17, Issue: 2. Pages: 267-74.Shantibhusan Senapati, Pallavi Chaturvedi, William G Chaney, Subhankar Chakraborty, Vinayaga S Gnanapragassam, Aaron R Sasson, Surinder K Batra et al.Several studies have reported aberrant expression of MUC4 in pancreatic cancer (PC), which is associated with tumorigenicity and metastasis. Mechanisms through which MUC4 promote metastasis of PC cells to distant organs are poorly defined.
  • Cancer (2010).Zhimin Tong, Subhankar Chakraborty, Bokyung Sung, Pooja Koolwal, Sukhwinder Kaur, Bharat B Aggarwal, Sendurai A Mani, Robert S Bresalier, Surinder K Batra, Sushovan Guha et al.BACKGROUND:: The authors previously reported that neutrophil gelatinase-associated lipocalin (NGAL) overexpression significantly blocked invasion and angiogenesis of pancreatic ductal adenocarcinoma (PDAC). They also demonstrated a loss of NGAL expression in the advanced stages of PDAC. However, little is known regarding the mechanisms of NGAL regulation in PDAC. Because the epidermal growth factor (EGF)-EGF receptor (EGFR) axis is up-regulated significantly in PDAC, they examined EGF-mediated NGAL regulation in these cells. METHODS:: The NGAL-positive cell lines AsPC-1 and BxPC-3 were used as a model system. Quantitative real-time polymerase chain reaction (RT-PCR), Western blot analysis, and immunofluorescence studies were used to investigate EGF-mediated effects on NGAL expression. E-cadherin expression was manipulated using lentiviral overexpression or small hairpin RNA constructs. NGAL promoter activity was assessed by luciferase-reporter assay and electrophoretic mobility shift assay. RESULTS:: NGAL expression was positively associated with tumor differentiation and was down-regulated significantly after EGF treatment along with a concomitant reduction of E-cadherin expression in PDAC cells. E-cadherin down-regulation was partly through the EGFR-dependent mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) (MEK-ERK) signaling pathway. In addition, E-cadherin down-regulation reduced NGAL expression in PDAC cells, whereas overexpression of E-cadherin led to increased NGAL expression and partly rescued the inhibition of NGAL expression by EGF. Furthermore, EGF, in part through E-cadherin, reduced NGAL promoter activity by blocking nuclear factor kB (NF-kB) activation. CONCLUSIONS:: The current study demonstrated for the first time that EGF potently blocked NGAL expression in PDAC cells. This effect was mediated in part through activation of the EGFR-MEK-ERK signaling pathway, which, in turn, down-regulated E-cadherin with a subsequent reduction in NF-kB activation. These findings illustrate a novel mechanism by which EGF regulates NGAL expression in PDAC. Cancer 2011;. 2010 American Cancer Society.
  • Transcriptional profiling of peripheral blood mononuclear cells in pancreatic cancer patients identifies novel genes with potential diagnostic utility.
    PloS one (2011). Volume: 6, Issue: 2. Pages: e17014.Michael J Baine, Subhankar Chakraborty, Lynette M Smith, Kavita Mallya, Aaron R Sasson, Randall E Brand, Surinder K Batra et al.It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility.
  • Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin.
    British journal of cancer (2011). Volume: 104, Issue: 6. Pages: 1038-48.S Rachagani, S Senapati, S Chakraborty, M P Ponnusamy, S Kumar, L M Smith, M Jain, S K Batra et al.Pancreatic cancer (PC) harbours an activated point mutation (Kras(G12D)) in the Kras proto-oncogene that has been demonstrated to promote the development of PC.
  • Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature.
    Anti-cancer drugs (2009). Volume: 20, Issue: 7. Pages: 634-8.Edward James, Maeve G Waldron-Lynch, Muhammad Wasif Saif et al.Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 have been proven to predict a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. There is evidence of in vivo therapeutic response to the cross-linking agents; such as mitomycin C (MMC) in BRCA2 mutated pancreatic cell lines. We present the ‘first patient’ who achieved a prolonged survival on irinotecan, a topoisomerase I poison, administered alone and then in combination with cetuximab. Our patient presented at the age of 71 years with a dual diagnosis of prostate carcinoma and pancreatic carcinoma on the background of a significant family history of cancer. On genetic testing, he was found to have the common Ashkenazi Jewish BRCA2 mutation, 6174delT. To date, he has received 22 cycles of docetaxel, capecitabine, and gemcitibine followed by single agent irinotecan every 3 weeks for 27 cycles, and then weekly cetuximab was added to the regimen at cycle 28. His disease then remained stable for an additional 13 months. He did not have mutated KRAS. MMC and oxaliplatin was then introduced upon progression. His current treatment is MMC plus irinotecan as oxaliplatin was removed because of a hypersensitivity reaction. This patient is stable with an Eastern Cooperative Oncology Group performance status of 0, four and a half years (56 months) after his initial diagnosis. DNA topoisomerases are nuclear enzymes responsible for the regulation of DNA topology. They are involved in basic DNA transactions during replication, transcription, and recombination. BRCA2-deficient human cells are deficient in the repair of double-strand breaks and DNA cross-links through homologous recombination. Active poisons of topoisomerase I include derivatives of camptothecin. Our case is the first clinical piece of evidence that demonstrates an increased sensitivity to camptothecin-11 and a reduced topoisomerase I relaxation activity in BRCA2 associated pancreatic cancer. This case shows that patients with metastatic pancreatic carcinoma and BRCA2 mutations may have disease that is biologically more chemosensitive and consequently prolong survival despite prognostically unfavorable disease.
  • Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy.
    Cancer biology & therapy (2011). Volume: 12, Issue: 3. Pages: 165-8.Amir Sonnenblick, Luna Kadouri, Liat Appelbaum, Tamar Peretz, Michal Sagi, Yael Goldberg, Ayala Hubert et al.Carriers of a germline mutation in the BRCA genes, in particular BRCA2, have an increased risk of developing pancreatic adenocarcinoma when compared with the general population. While the addition of cisplatin to gemcitabine did not produce survival benefit compared to single-agent gemcitabine in prospective trials it is postulated that the addition of DNA cross-linking agent such as cisplatin to standard gemcitabine chemotherapy should be considered in known BRCA mutation carriers. We report a case of pancreatic adenocarcinoma arising in a 60-year-old carrier of a rare BRCA2 (1153insertionT) germline mutation. The patient received gemcitabine without any response and actually progression of the disease had occurred. Therefore cisplatin was added in combination with gemcitabine. A dramatic complete response to therapy was encountered with no evidence of disease in both CT scans and markers (CA19-9). In conclusion, in patients with known BRCA mutation associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin should be considered. Physicians should consider BRCA mutation testing when the diagnosis of pancreatic cancer is established, especially when the patient belongs to an ethnic group where founder mutations exist, and/or there is strong personal or family history of cancer. This may be applied also to other metastatic tumors diagnosed in BRCA1/2 carriers.
  • MicroRNA-10b is overexpressed in pancreatic cancer, promotes its invasiveness, and correlates with a poor prognosis.
    Surgery (2011). Volume: 150, Issue: 5. Pages: 916-22.Kohei Nakata, Kenoki Ohuchida, Kazuhiro Mizumoto, Tadashi Kayashima, Naoki Ikenaga, Hiroshi Sakai, Cui Lin, Hayato Fujita, Takao Otsuka, Shinichi Aishima, Eishi Nagai, Yoshinao Oda, Masao Tanaka et al.MicroRNAs (miRNAs) have been gaining attention as new, key molecules that contribute to carcinogenesis. In pancreatic cancer, previous profiling analyses of miRNA expression have shown that several miRNAs are differently expressed in normal and cancerous tissues. Several pancreatic cancer-specific miRNAs differed, however, in each analysis.
  • The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer.
    Journal of cellular biochemistry (2011).Niranjan Awasthi, Peter L Yen, Margaret A Schwarz, Roderich E Schwarz et al.Gemcitabine has limited clinical benefits for pancreatic ductal adenocarcinoma (PDAC). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in PDAC. We investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival experiments were performed in murine xenografts. BEZ235 caused a decrease in phospho-AKT and phospho-mTOR expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. BEZ235 inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on proliferation inhibition were observed in the BEZ235-gemcitabine combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38?cells. BEZ235, alone or in combination with gemcitabine and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38?cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and gemcitabine monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235?+?gemcitabine (30 days, p?=?0.007), BEZ235?+?EMAP (27 days, p?=?0.02), gemcitabine?+?EMAP (31 days, p?=?0.001) and BEZ235?+?gemcitabine +EMAP (33 days, p?=?0.004). BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of gemcitabine and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment. J. Cell. Biochem. ? 2011 Wiley Periodicals, Inc.
  • PPAR-{gamma} potentiates anticancer effects of gemcitabine on human pancreatic cancer cells.
    International journal of oncology (2011).
    Hironori Koga, Karuppaiyah Selvendiran, Ramadoss Sivakumar, Takafumi Yoshida, Takuji Torimura, Takato Ueno, Michio Sata et al.
    In order to improve the prognosis of patients with unresectable pancreatic cancer, there is an urgent need for enhancement of the anticancer effect of gemcitabine (Gem), a first-line drug for the disease. Here, we demonstrated that ligands for peroxisome proliferator-activated receptor {gamma} (PPAR-{gamma}) such as pioglitazone (Pio) and rosiglitazone potentiated the cytotoxic action of Gem on human pancreatic cancer cells in a dosage-dependent manner. Notably, the synergistic effect was PPAR-{gamma}-dependent, since the effect was augmented by PPAR? overexpression and was attenuated by both a PPAR-{gamma} inhibitor (GW9662) and PPAR-{gamma}-specific siRNA. To further increase the collaborative effect, the histone deacetylase (HDAC) inhibitor valproic acid (VPA), a known potentiator for PPAR? function, was added to the combinatorial treatment, robustly inducing apoptosis mediated by highly expressed death receptors, including Fas/CD95 and DR5. In xenograft tumor experiments in nude mice, Gem plus Pio significantly suppressed tumor growth as compared with the control treatment, while Gem-only treatment did not. Triple treatment with Gem, Pio, and VPA failed to demonstrate a significant antitumor effect when compared with Gem plus Pio in the current setting. Considered together, Gem plus PPAR-{gamma} ligands, including Pio, may have therapeutic advantage in the treatment of advanced pancreatic cancer. Since Pio is widely used in the treatment of diabetes mellitus, it may become a feasible partner of Gem-based chemotherapy, fine-tuning the strength of the therapy in a dosage-dependent fashion.
  • Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma.
    International journal of cancer. Journal international du cancer (2011).Jan Sperveslage, Sunna Frank, Carola Heneweer, Jan Egberts, Bodo Schniewind, Malte Buchholz, Frank Bergmann, Nathalia Giese, Johanna Munding, Stephan Hahn, Holger Kalthoff, G?nter Kl?ppel, Bence Sipos et al.CCR7 expression on tumor cells promotes lymphatic spread in several malignant tumors. However, a comprehensive characterization of the CCL19/CCL21-CCR7 axis in pancreatic ductal adenocarcinoma (PDAC), which is known for its high rates of lymph node metastases, is still lacking. CCR7 mRNA and CCR7 protein were found to be expressed in spheroid cultures of all 6 examined PDAC cell lines. In migration assays CCR7 expressing PDAC cells showed enhanced migration towards CCL19 and CCL21, the two ligands of CCR7. In an orthotopic nude mouse model, CCR7 transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph vessel invasion and lymph node metastases than mock transfected cells. In an analysis using quantitative real-time PCR CCR7 showed 4-fold overexpression in microdissected PDAC cells compared to normal duct cells. Moderate-to-strong immunohistochemical CCR7 expression, found in 58/121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph node metastases. The evaluation of CCL21 expression by immunofluorescence staining revealed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared to lymph vessels in disease-free pancreata. In conclusion, our study revealed strong evidence that lack of CCR7 impairs the metastatic potential of PDAC. Lymph vessel invasion by CCR7 expressing PDAC cells may be additionally enhanced by upregulation of CCL21 in tumor-associated lymph vessels, representing a previously unknown factor of lymphatic spread. ? 2011 UICC.
  • Apoptosis and Expression of the Bcl-2 Family of Proteins and P53 in Human Pancreatic Ductal Adenocarcinoma.
    Medical principles and practice : international journal of the Kuwait University, Health Science Centre (2011).Dong Chen, Xuefeng Zheng, Dalu Kang, Bomin Yan, Xiaoyi Liu, Yuan Gao, Kejun Zhang et al.Objective: The purpose of this study was to clarify the association between P53 and the Bcl-2 family (Bcl-2, Bax, Bcl-xL, Bcl-xS) expression and apoptosis in pancreatic ductal adenocarcinoma (PDAC). Subjects and Methods: A total of 70 patients with PDAC were studied. The expression of P53 protein in PDAC was assessed using the immunohistochemical method, which categorized the PDAC patients into two groups: group 1: 36 cases with immunonegative P53(-), and group 2: 34 cases with immunopositive P53(+). The expression of Bcl-2, Bax, Bcl-xL, and Bcl-xS in the 70 PDAC cases was detected by immunohistochemical and Western blotting methods. The apoptotic index (AI) was also measured in these samples by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The relation between P53 and the Bcl-2 protein family and apoptosis was then evaluated. Results: Bcl-2 and Bcl-xS expression was significantly associated with P53 (p < 0.05). No clear associations were found among P53, Bax and Bcl-xL expression (p > 0.05). The AI of groups 1 and 2 was 12.1 ? 2.47 and 8.1 ? 1.48, respectively (p = 0.023). There was no relationship between AI and Bcl-2, Bax, Bcl-xL and Bcl-xS expression (p > 0.05, respectively). Bcl-2/Bax ratio was significantly associated with AI (p < 0.01). Conclusion: Bcl-2 and Bcl-xS represent significant anti- and proapoptotic proteins, respectively, modulated through a P53-dependent pathway in PDAC, and P53 modulated apoptosis mainly through Bcl-2/Bax ratio.
  • First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2011).Timothy A Yap, Li Yan, Amita Patnaik, Ivy Fearen, David Olmos, Kyriakos Papadopoulos, Richard D Baird, Liliana Delgado, Adekemi Taylor, Lisa Lupinacci, Ruth Riisnaes, Lorna L Pope, Simon P Heaton, George Thomas, Michelle D Garrett, Daniel M Sullivan, Johann S de Bono, Anthony W Tolcher et al.PURPOSE: AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. PATIENTS AND METHODS: Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss.ResultsThirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. CONCLUSION: MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.
  • Chemotherapeutic properties of phospho-nonsteroidal anti-inflammatory drugs, a new class of anticancer compounds.
    Cancer research (2011).Liqun Huang, Gerardo G Mackenzie, Yu Sun, Nengtai Ouyang, Gang Xie, Kvetoslava Vrankova, Despina Komninou, Basil Rigas et al.Non-steroidal anti-Inflammatory drugs (NSAIDs) exhibit antineoplastic properties, but conventional NSAIDs do not fully meet safety and efficacy criteria for use as anti-cancer agents. In this study, we evaluated the chemotherapeutic efficacy of five novel phospho-NSAIDs, each of which includes in addition to the NSAID moiety a diethylphosphate linked through a butane moiety. All five compounds inhibited the growth of human breast, colon and pancreatic cancer cell lines with micromolar potency. In vivo investigations confirmed the antitumor activity of phospho-aspirin (PA) and phospho-sulindac (PS) in inhibiting tumor growth in established human xenograft models, where cell proliferation was suppressed and apoptosis enhanced in the absence of detectable animal toxicity. Notably, all of the phospho-NSAIDs tested induced reactive oxygen and nitrogen species in cultured cells, with PA and PS inducing detectable levels of oxidative stress in vivo that were associated positively with apoptosis and negatively with proliferation. Potentially explaining these effects, all of the phospho-NSAIDs tested also inhibited the thioredoxin system and the redox sensitive transcription factor NF-?B. Taken together, our findings demonstrate the strong anticancer efficacy and promising safety of phospho-NSAIDs in preclinical models of breast, colon and pancreatic cancer, suggesting further evaluation as anticancer agents.
  • Association between DNA-repair polymorphisms and survival in pancreatic cancer patients treated with combination chemotherapy.
    Pharmacogenomics (2011).Elisa Giovannetti, Paola Pacetti, Michele Reni, Leticia G Leon, Andrea Mambrini, Enrico Vasile, Michele Ghidini, Niccola Funel, Matteo Lucchesi, Stefano Cereda, Godefridus J Peters, Maurizio Cantore et al.Aim: This multicenter study evaluated the association of 11 candidate polymorphisms in eight genes with outcome of pancreatic cancer patients treated with the equivalent polychemotherapeutic regimens: cisplatin/epirubicin/capecitabine/gemcitabine, cisplatin/docetaxel/capecitabine/gemcitabine and gemcitabine/capecitabine plus epirubicin/cisplatin intra-arterial infusion. Patients & methods: Towards this end, polymorphisms were assessed in DNA from 122 pancreatic cancer stage-III/IV patients, and their associations with toxicity/response and progression-free survival (PFS) and overall survival were evaluated using Pearson-?(2) and log-rank test. Results: Patients harboring XPD Gln751Gln, XPD Asp312Asn + Asn312Asn or XRCC1 Arg399Gln + Gln399Gln genotypes had a worse prognosis. XPD Gln751Gln (hazard ratio: 1.9; p = 0.003), as well as a combination of over two risk genotypes (hazard ratio: 2.7; p < 0.001), emerged as independent predictors for death risk at multivariate analysis. No correlations were observed with toxicity. Conversely, XPD Gln751Gln was associated with shorter PFS, while the lack of association with overall survival/PFS in gemcitabine monotherapy-treated patients suggested its role only for platinum-based regimens. Conclusion: Polymorphisms of DNA-repair genes appear to be candidate biomarkers of primary resistance to gemcitabine/cisplatin-based polychemotherapeutic regimens. The relatively small sample size, coupled with the retrospective and exploratory design of the present study, imply that these results should be considered as hypothesis generators, and should be further evaluated in larger and adequately designed retrospective/prospective studies. Original submitted 26 April 2011; Revision submitted 20 July 2011.
  • MUC13 mucin augments pancreatic tumorigenesis.
    Molecular cancer therapeutics (2011).Subhash C Chauhan, Mara C Ebeling, Diane M Maher, Michael D Koch, Akira Watanabe, Hiroyuki Aburatani, Yuhlong Lio, Meena Jaggi et al.The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early diagnosis and underlying molecular mechanisms of its aggressive pathogenesis. While MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian, gastric and colon cancer, its role in pancreatic cancer is unknown. Herein, we have investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (p<0.005) higher in cancer samples compared to normal/non-neoplastic pancreatic tissues. For functional analyses, full length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (p<0.05) increase in cell motility, invasion, proliferation, and anchorage dependent/independent clonogenicity, while decreasing cell-cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (p<0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the up-regulation/phosphorylation of HER2, p21-activated kinase1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and S100A4 (metastasin) and suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by shRNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK and S100A4 and up-regulation of p53. MUC13 suppression also significantly (p<0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target.
  • A Polymeric Nanoparticle Encapsulated Small Molecule Inhibitor of Hedgehog Signaling (NanoHHI) Bypasses Secondary Mutational Resistance to Smoothened Antagonists.
    Molecular cancer therapeutics (2011).

    Venugopal Chenna, Chaoxin Hu, Dipankar Pramanik, Blake T Aftab, Collins Karikari, Nathaniel R Campbell, Seung-Mo Hong, Ming Zhao, Michelle A Rudek, Saeed R Khan, Charles M Rudin, Anirban Maitra et al.

    Aberrant activation of the Hedgehog (Hh) signaling pathway is one of the most prevalent abnormalities in human cancer. Tumors with cell autonomous Hh activation (e.g., medulloblastomas) can acquire secondary mutations at the Smoothened (Smo) antagonist binding pocket, which render them refractory to conventional Hh inhibitors. A class of Hh Pathway Inhibitors (HPIs) has been identified that block signaling downstream of Smo; one of these compounds, HPI-1, is a potent antagonist of the Hh transcription factor Gli1, and functions independent of upstream components in the pathway. Systemic administration of HPI-1 is challenging due to its minimal aqueous solubility and poor bioavailability. We engineered a polymeric nanoparticle from poly(lactic-co-glycolic acid) (PLGA) conjugated with polyethylene glycol (PEG), encapsulating HPI-1 (NanoHHI). NanoHHI particles have an average diameter ~60nM, forms uniform aqueous suspension, and improved systemic bioavailability compared to the parent compound. In contrast to the prototype targeted Smo antagonist, HhAntag (Genentech), NanoHHI markedly inhibits the growth of allografts derived from Ptch-/+;Trp53-/- mouse medulloblastomas that harbor a SmoD477G binding site mutation (P<0.001), which is accompanied by significant downregulation of mGli1, as well as bona fide Hh target genes (Akna, Cltb, Olig2). Notably, NanoHHI combined with gemcitabine also significantly impedes the growth of orthotopic Pa03C pancreatic cancer xenografts that have a ligand-dependent, paracrine mechanism of Hh activation, when compared to gemcitabine alone. No demonstrable hematological or biochemical abnormalities were observed with NanoHHI administration. NanoHHI should be amenable to clinical translation in settings where tumors acquire mutational resistance to current Smo antagonists.

  • Sonic hedgehog signaling pathway in pancreatic cystic neoplasms and ductal adenocarcinoma.
    Pancreas (2007). Volume: 34, Issue: 3. Pages: 340-6.Maw-Sen Liu, Po-Yi Yang, Ta-Sen Yeh et al.Hedgehog (Hh) signaling is an important mediator of tumorigenesis of pancreatic ductal adenocarcinoma (PA). It is intriguing to explore whether Hh signaling is also involved in pancreatic cystic neoplasms, which are phenotypically different from PA.
  • Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells.
    PloS one (2010). Volume: 5, Issue: 1. Pages: e8824.Kazumasa Nakamura, Junpei Sasajima, Yusuke Mizukami, Yoshiaki Sugiyama, Madoka Yamazaki, Rie Fujii, Toru Kawamoto, Kazuya Koizumi, Kazuya Sato, Mikihiro Fujiya, Katsunori Sasaki, Satoshi Tanno, Toshikatsu Okumura, Norihiko Shimizu, Jun-ichi Kawabe, Hidenori Karasaki, Toru Kono, Masaaki Ii, Nabeel Bardeesy, Daniel C Chung, Yutaka Kohgo et al.The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells.
  • Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis.
    Proceedings of the National Academy of Sciences of the United States of America (2009). Volume: 106, Issue: 11. Pages: 4254-9.Hua Tian, Christopher A Callahan, Kelly J DuPree, Walter C Darbonne, Christina P Ahn, Suzie J Scales, Frederic J de Sauvage et al.The Hedgehog (Hh) pathway has been implicated in pancreatic cancer but its role remains controversial. To delineate the cell populations able to respond to Hh ligand stimulation, we expressed an oncogenic allele of Smoothened (SmoM2) to cell autonomously activate Hh signaling in the mouse pancreas. Surprisingly, we found that expression of SmoM2 in epithelial cells was not able to activate the pathway and had no impact on pancreatic development or neoplasia. In contrast, activation of Smo in the mesenchyme led to Hh pathway activation, indicating that only the tumor stroma is competent to transduce the Hh signal. Using a Ptc-LacZ reporter mouse, we show that Hh signaling is active in stromal cells surrounding Hh-expressing tumor epithelium in various mouse pancreatic cancer models. Activation of the Hh pathway in the tumor stroma of human pancreatic and metastatic cancer specimens was confirmed by quantitative RT-PCR of microdissected tissue samples. These data support a paracrine model of Hh-mediated tumorigenesis, in which tumor cells secrete Hh ligand to induce tumor-promoting Hh target genes in adjacent stroma.

About Mark Fortner

I write software for scientists doing drug discovery and cancer research. I'm interested in Design Thinking, Agile Software Development, Web Components, Java, Javascript, Groovy, Grails, MongoDB, Firebase, microservices, the Semantic Web Drug Discovery and Cancer Biology.
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