Adjuvant treatment of pancreatic cancer in 2009: where are we? Highlights from the 45th ASCO annual meeting. Orlando, FL, USA. May 29-June 2, 2009.

JOP. 2009;10(4):373-7

Authors: Saif MW

Despite attempted curative resection of localized pancreatic adenocarcinoma, most patients succumb a recurrence and die of their disease. The Gastrointestinal Tumor Study Group, European Organization for Research and Treatment of Cancer, and European Study Group for Pancreatic Cancer trials have suggested the benefit of adjuvant therapy. However, the relatively few randomized trials available have not established a definite standard of care due to study limitations. Although these trials, and the recently published Charité Onkologie (CONKO)-001 trial, have shown a definite advantage of adjuvant chemotherapy, the most effective chemotherapy and the role of radiation therapy remain unclear. This review will discuss the data available from reported trials of adjuvant therapy in pancreatic cancer, especially the results of the ESPAC-3 study presented at the annual meeting of ASCO 2009, and consider future directions for clinical trials.

PMID: 19581737 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

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

Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases.

J Biomed Biotechnol. 2009;2009:451084

Authors: Roth M, Zhong J, Tamm M, Szilard J Therapy with hyperthermal chemotherapy in pleural diffuse malignant mesothelioma had limited benefits for patients. Here we investigated the effect of heat stress on heat shock proteins (HSP), which rescue tumour cells from apoptosis. In human mesothelioma and mesothelial cells heat stress (39-42 degrees C) induced the phosphorylation of two mitogen activated kinases (MAPK) Erk1/2 and p38, and increased Hsp40, and Hsp70 expression. Mesothelioma cells expressed more Hsp40 and were less sensitive to heat stress compared to mesothelial cells. Inhibition of Erk1/2 MAPK by PD98059 or by Erk1 siRNA down-regulated heat stress-induced Hsp40 and Hsp70 expression and reduced mesothelioma cell survival. Inhibition of p38MAPK by SB203580 or siRNA reduced Hsp40, but not Hsp70, expression and also increased mesothelioma cell death. Thus hyperthermia combined with suppression of p38 MAPK or Hsp40 may represent a novel approach to improve mesothelioma therapy.

PMID: 19551156 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: mesothelioma

BMJ. 2009;339:b2862

Authors: Sweeney K, Toy L,Cornwell J

Professor Kieran Sweeney was diagnosed with malignant mesothelioma at age 57. He describes here his thoughts on his interactions with the health professionals who care for him.

PMID: 19684101 [PubMed - in process]

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

Insulin-like growth factor binding protein-5 influences pancreatic cancer cell growth.

World J Gastroenterol. 2009 Jul 21;15(27):3355-66

Authors: Johnson SK,

Haun RS AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).

METHODS: The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen activated protein kinase and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.

RESULTS: After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.

CONCLUSION: These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth. PMID: 19610136 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Related Articles PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through the activation of the met tyrosine kinase receptor gene.

J Biol Chem. 2009 Aug 3;

Authors: Mascarenhas JB, Young KP, Littlejohn EL, Yoo BK, Salgia R, Lang D

Tumors of the exocrine pancreas have a poor prognosis. Several proteins are over-expressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. This data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to pro-tumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.

Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen.

Ann N Y Acad Sci. 2009 Feb;1155:99-111

Authors: Lazarus P, Blevins-Primeau AS, Zheng Y, Sun D

Tamoxifen (TAM) is a selective estrogen receptor modulator that is widely used in the prevention and treatment of estrogen receptor-positive (ER(+)) breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with Tamoxifen (TAM) for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up and occurrence of contralateral breast cancer. However, in patients treated with TAM there is substantial interindividual variability in the development of resistance to TAM therapy, and in the incidence of Tamoxifen (TAM)-induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. This article will focus on the UDP glucuronosyltransferases, a family of metabolizing enzymes that are responsible for the deactivation and clearance of TAM and TAM metabolites, and how interindividual differences in these enzymes may play a role in patient response to Tamoxifen (TAM).

PMID: 19250197 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: cancer endometrial

Solitary true cyst of the pancreas in adults. A report of two cases.

JOP. 2009;10(4):429-31

Authors: Carboni F, Mancini P, Lorusso R, Santoro E

CONTEXT: Solitary true cysts of the pancreas in adults are extremely rare and only few cases have been reported in the literature. The etiology and natural history of these lesions remain unknown and treatment is not standardized. We describe two additional resected cases.

CASE REPORTS: The first patient was a young woman with an incidental 3 cm cyst located in the pancreatic head who underwent enucleation. The second patient was a young woman with a large 8 cm symptomatic cyst located in the pancreatic tail who underwent a laparoscopic spleen-preserving distal pancreatectomy. Histological examination revealed fibrous walls lined by a monolayer of cuboidal epithelium in both cases.

CONCLUSIONS: A preoperative work-up alone does not always allow an accurate diagnosis, but it is useful in determining lesion characteristics and guiding therapeutic decision making. When surgery is indicated, a limited resection is warranted in most cases. PMID: 19581750 [PubMed - in process]

Read Full Article pubmed: pancreatic cancer

Three Epigenetic Drugs Up-regulate Homeobox Gene Rhox5 in Cancer Cells through Overlapping and Distinct Molecular Mechanisms.

Mol Pharmacol. 2009 Aug 13;

Authors: Li Q, Bartlett DL, Gorry MC, O'Malley ME, Guo ZS

Epigenetic therapy of cancer utilizing inhibitors of DNA methyltransferases (DNMT) or/and histone deacetylases (HDAC) have shown promising results in preclinical models and are being investigated in clinical trials. Homeodomain proteins play important roles in normal development and carcinogenesis. In this study, we demonstrated for the first time that an epigenetic drug could upregulate homeobox genes in the Rhox family, including murine Rhox5, Rhox6, Rhox9 and human RhoxF1, RhoxF2 in breast, colon and other types of cancer cells. We examined the molecular mechanisms underlining selective induction of Rhox5 in cancer cells by three epigenetic drugs, 5-aza-2'-deoxycytidine (DAC; decitabine), arsenic trioxide (ATO) and MS-275 (entinostat). DAC induced Rhox5 mRNA expression from both distal and proximal promoters, while MS-275 and ATO induced gene expression from the distal promoter (Pd) only. DAC and ATO inhibited both DNMT1 and DNMT3B protein expression, while MS-275 significantly reduced DNMT3B protein. In contrast to DAC, neither MS-275 nor ATO induced DNA demethylation on the Pd region. All three drugs led to enhanced acetylation of histones H3 and H4 at the promoter region. The occupancy of the activating histone mark dimethylated lysine 4 of H3 (H3K4Me2) at Pd was enhanced by DAC and MS-275, but not ATO. Based on the fact that they modulate gene expression with different potencies through shared and distinct epigenetic mechanisms, these epigenetic drugs may possess great potential in different applications for epigenetic therapy of cancer and other diseases.

PMID: 19679824 [PubMed - as supplied by publisher]

Read Full Article pubmed: colon cancer