Authors: Cousin B, Ravet E, Poglio S, De Toni F, Bertuzzi M, Lulka H, Touil I, André M, Grolleau JL, Péron JM, Chavoin JP, Bourin P, Pénicaud L, Casteilla L, Buscail L, Cordelier P

BACKGROUND: Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC) spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC) on pancreatic tumor cell proliferation.

PRINCIPAL FINDINGS: Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate). ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth.

CONCLUSION: These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available. PMID: 19609435 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Autoimmune pancreatitis results from loss of TGFbeta signalling in S100A4-positive dendritic cells.

Gut. 2009 Sep;58(9):1267-74

Authors: Boomershine CS, Chamberlain A, Kendall P, Afshar-Sharif AR, Huang H, Washington MK, Lawson WE, Thomas JW, Blackwell TS, Bhowmick NA

BACKGROUND AND AIMS: Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model.

METHODS: A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor beta (TGFbeta) type II receptor, termed Tgfbr2(fspKO), was used to determine the direct role of TGFbeta in S100A4(+) cells. Immunohistochemical studies suggested that Tgfbr2(fspKO) mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination.

RESULTS: The Tgfbr2(fspKO) mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2(fspKO) mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2(fspKO) DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2(fspKO) DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells.

CONCLUSION: The development of mAIP in the Tgfbr2(fspKO) mouse model illustrates the role of TGFbeta in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4(+) DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis. PMID: 19625278 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Induction of necrosis and cell cycle arrest in murine cancer cell lines by Melaleuca alternifolia (tea tree) oil and terpinen-4-ol.

Cancer Chemother Pharmacol. 2009 Aug 13; Authors: Greay SJ, Ireland DJ, Kissick HT, Levy A, Beilharz MW, Riley TV, Carson CF

PURPOSE: To examine the in vitro anticancer activity of Melaleuca alternifolia (tea tree) oil (TTO), and its major active terpene component, terpinen-4-ol, against two aggressive murine tumour cell lines, AE17 mesothelioma and B16 melanoma.

METHODS: Effects of TTO and terpinen-4-ol on the cellular viability of two tumour cell lines and fibroblast cells were assessed by MTT assay. Induction of apoptotic and necrotic cell death was visualised by fluorescent microscopy and quantified by flow cytometry. Tumour cell ultrastructural changes were examined by transmission electron microscopy and changes in cell cycle distribution were assessed by flow cytometry, with changes in cellular morphology monitored by video time lapse microscopy.

RESULTS: TTO and terpinen-4-ol significantly inhibited the growth of two murine tumour cell lines in a dose- and time-dependent manner. Interestingly, cytotoxic doses of TTO and terpinen-4-ol were significantly less efficacious against non-tumour fibroblast cells. TTO and terpinen-4-ol induced necrotic cell death coupled with low level apoptotic cell death in both tumour cell lines. This primary necrosis was clarified by video time lapse microscopy and also by transmission electron microscopy which revealed ultrastructural features including cell and organelle swelling following treatment with TTO. In addition, both TTO and terpinen-4-ol induced their inhibitory effect by eliciting G1 cell cycle arrest.

CONCLUSION: TTO and terpinen-4-ol had significant anti-proliferative activity against two tumour cell lines. Moreover, the identification of primary necrotic cell death and cell cycle arrest of the aggressive tumour cells highlights the potential anticancer activity of TTO and terpinen-4-ol.

PMID: 19680653 [PubMed - as supplied by publisher]

Read Full Article pubmed: mesothelioma and ((e...

Clinical Significance of Skin Toxicity due to EGFR-Targeted Therapies.

J Oncol. 2009;2009:849051

Authors: Giovannini M, Gregorc V, Belli C, Roca E, Lazzari C, Viganò MG, Serafico A, Villa E

Many small molecules and monoclonal antibodies blocking the activity of Epidermal Growth factor receptor (EGFR) have been developed and have shown clinical activity in patients with non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC), and are in clinical development for a range of other solid tumors. The toxicity profile of such agents is characterized by a typical pattern of cutaneous reactions. In this paper we reviewed the current available data regarding the clinical significance of skin reaction due to EGFR targeted agents. We show that skin toxicity can be considered as predictive marker of response to such drugs and that it is not disease specific; however its potential prognostic value is still to be proven.

PMID: 19584908 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Functional enhancers at the gene-poor 8q24 cancer-linked locus.

PLoS Genet. 2009 Aug;5(8):e1000597

Authors: Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff P, Oh W, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman M, Tanay A, Coetzee GA

Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

PMID: 19680443 [PubMed - in process]

Read Full Article pubmed: colon cancer

S-1: a new oral fluoropyrimidine in the treatment of patients with advanced non-small-cell lung cancer.

Clin Lung Cancer. 2009 Jul;10(4):290-4

Authors: Okamoto I, Fukuoka M

S-1 (also known as TS-1; Taiho Pharmaceutical Co. Ltd.; Tokyo, Japan) is a new oral fluoropyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1. Single-agent S-1 has demonstrated marked activity against non-small-cell lung cancer (NSCLC) as well as a broad array of other solid tumors, including gastric, colorectal, breast, cervical, and pancreatic cancers. This comprehensive review summarizes the results of previous clinical studies and describes ongoing clinical trials of S-1 in advanced NSCLC. S-1 combined with platinum compounds, irinotecan, and gemcitabine has produced promising results in terms of feasibility, safety, and effectiveness. Available data have stimulated further research, including phase III trials for the first-line treatment of advanced NSCLC.

Malignant pleural mesothelioma: medical treatment update.

Clin Lung Cancer. 2009 Mar;10(2):112-7

Authors: Vorobiof DA, Mafafo K

Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available.

Influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival.

Can J Surg. 2009 Aug;52(4):E79-E86

Authors: Simunovic M, Rempel E, Thériault ME, Baxter NN, Virnig BA, Meropol NJ, Levine MN

BACKGROUND: There has been minimal research on the influence of delays for cancer treatments on patient outcomes. We measured the influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival.

METHODS: We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare databases (1993-1996) to identify patients who underwent nonemergent colon cancer surgery. We assessed 2 time intervals: surgeon consult to hospital admission for surgery and first diagnostic test for colon cancer to hospital admission. Follow-up data were available to the end of 2003. We selected the time intervals to create patient groups with clinical relevance and they did not extend past 120 days.

RESULTS: We identified 7989 patients who underwent nonemergent colon cancer surgery. Median delays from surgeon consult to admission and from first diagnostic test to admission were 7 and 17 days, respectively. The odds of operative mortality were similar if the consult-to-admission interval was 22 days or more versus 1-7 days (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.6-1.8, p = 0.91) or if the test-to-admission interval was 43 days or more versus 1-14 days (OR 0.8, 95% CI 0.4-1.5, p = 0.51), respectively. For these same respective interval comparisons, disease-specific survival was not influenced by the consult-to-admission wait (hazard ratio [HR] 1.0, 95% CI 0.9-1.2, p = 0.91) or the test-to-admission wait (HR 1.0, 95% CI 0.8-1.1, p = 0.63). The risk of death was slightly greater if the consult-to-admission interval was 22 or more days versus 1-7 days (HR 1.1, 95% CI 1.0-1.2, p = 0.013) and if the test-to-admission interval was 43 days or more versus 1-14 days (HR 1.2, 95% CI 1.1-1.3, p = 0.003). CONCLUSION: It is unlikely that delays to nonemergent colon cancer surgery longer than 3 weeks from initial surgical consult or longer than 6 weeks from first diagnostic test negatively impact operative mortality, disease-specific survival or overall survival.

PMID: 19680502 [PubMed - as supplied by publisher]

Read Full Article pubmed: colon cancer

Pancreatectomy for pancreatic cancer with reference to combined resection of the vessels, twenty nine year experience by a single surgeon.

Keio J Med. 2009 Jun;58(2):103-9

Authors: Sugiura Y, Horio T, Aiko S, Ishizuka T, Kumano I, Kato Y, Kato A, Kitajima M

Between 1978 and 2007 one hundred and seven patients consecutively underwent resection for primary pancreatic adenocarcinoma. There were 28 pN0 patients, 41 pN1 and 37 pN2 or more (one unknown). Combined resection of the portal vein was performed in 62 out of 107 patients (58%). The hepatic artery in 10 patients, superior mesenteric artery in 8 patients and celiac trunk in 7 patients were also resected additionally to the portal vein. The 5-year survival rate and 10-year survival rate of all 107 cases were 12.1% and 2.8% respectively. The 5-year survival rate of the pN0 group was 37%, significantly better than the 14% 5-year survival rate in the pN1 group (p=0.043). Of 69 patients with pN0 or pN1, 38 patients underwent combined resection of the portal vein. There was not significant difference between the 24% 5-year survival rate in the group without the portal vein resection and the 19% 5-year survival rate in the group with portal vein resection. The 20% 5-year survival rate of the portal vein only group and the 5-year survival rate of both the portal vein and hepatic artery group were the same. The groups of the further resection of the superior mesenteric artery and of the celiac trunk showed no long-term survival. It is concluded that aggressive combined resection of the portal vein or additional resection of the hepatic artery be feasible for a survival benefit in pN0 and pN1 diseases.

PMID: 19597306 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.

PLoS One. 2009;4(5):e5735

Authors: Lubin M, Lubin A

BACKGROUND: The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5'-deoxy-5'-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are then converted to adenine nucleotides and methionine. This distinct difference between normal MTAP-positive cells and tumor MTAP-negative cells led to several proposals for therapy. We offer a novel strategy in which both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP), 6-methylpurine (MeP), or 2-fluoroadenine (F-Ade), are administered. In MTAP-positive cells, abundant adenine, generated from supplied MTA, competitively blocks the conversion of an analog, by adenine phosphoribosyltransferase (APRT), to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA cannot generate adenine; hence conversion of the analog is not blocked.

PRINCIPAL FINDINGS: We show that this combination treatment--adenine analog plus MTA--kills MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF) are protected. In co-cultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 is inhibited or killed, while HF cells proliferate robustly. 5-Fluorouracil (5-FU) and 6-thioguanine (6-TG) may also be used with our strategy. Though neither analog is activated by APRT, in MTAP-positive cells, adenine produced from supplied MTA blocks conversion of 5-FU and 6-TG to their toxic nucleotide forms by competing for 5-phosphoribosyl-1-pyrophosphate (PRPP). The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-negative tumors, may produce a significantly improved therapeutic index.

CONCLUSION: We describe a selective strategy to kill tumor cells lacking MTAP.

PMID: 19478948 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: mesothelioma

Related Articles The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews.

BMC Cancer. 2009 Jul 29;9(1):256

Authors: Lee PN, Hamling J

ABSTRACT:BACKGROUND: Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60-80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.