Survival after resection for ductal adenocarcinoma of the pancreas

Sperti, Cosimo; Pasquali, Claudio; Piccoli, Antônio; Pedrazzoli, Sergio

doi:10.1002/bjs.1800830512

Cited by 220 publications

(156 citation statements)

References 30 publications

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“…In addition, perineural invasion has been implicated in the pain syndrome that affects the majority of PDAC patients (5,6). A mechanical concept for perineural invasion by pancreatic cancer cells suggests a preferential penetration of tumor cells into the soft perineurium compared with the dense desmoplastic pancreatic tumor microenvironment (8).…”

Section: Discussionmentioning

confidence: 99%

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Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Abiatari

DeOliveira

Kerkadze

et al. 2009

Molecular Cancer Therapeutics

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Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor β (ARHGDIβ) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDIβ mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDIβ using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDIβ.

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Section: Discussionmentioning

confidence: 99%

“…Besides systemic spread, perineural invasion is one of the most significant predictors of poor prognosis (3,(5)(6)(7). Perineural invasion is a specific route of spread in PDAC.…”

Section: Introductionmentioning

confidence: 99%

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Abiatari

DeOliveira

Kerkadze

et al. 2009

Molecular Cancer Therapeutics

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“…However, surgery is not a viable option for most pancreatic cancer patients. 3 Cancers arise as a result of specific genetic changes in a handful of oncogenes and tumor suppressor genes. Four pivotal molecular events characterize pancreatic ductal adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

et al. 2005

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An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1a (HIF-1a) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1a m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1a protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF1a-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

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“…3 Mainly due to the difficulty in early detection and frequent metastatic dissemination, the 5-year survival rate for pancreatic cancer patients remains below 5%. 3,4 Considering that vascular involvement, lymph node metastasis, and neural invasion have been proposed as prognostic factors, [5][6][7] it seems that metastasis is responsible for the aggressive behavior of pancreatic cancer. Pancreatic cancer appears to acquire genetic aberrations with successive alteration of genes involved in the regulation of cell proliferation.…”

mentioning

confidence: 99%

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

Yamazaki

Takamura

Masugi

et al. 2009

Laboratory Investigation

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Pancreatic cancer has the worst prognosis among cancers due to the difficulty of early diagnosis and its aggressive behavior. To characterize the aggressiveness of pancreatic cancers on gene expression, pancreatic cancer xenografts transplanted into severe combined immunodeficient mice served as a panel for gene-expression profiling. As a result of profiling, the adenylate cyclase-associated protein 1 (CAP1) gene was shown to be overexpressed in all of the xenografts. The expression of CAP1 protein in all 73 cases of pancreatic cancer was recognized by immunohistochemical analyses. The ratio of CAP1-positive tumor cells in clinical specimens was correlated with the presence of lymph node metastasis and neural invasion, and also with the poor prognosis of patients. Immunocytochemical analyses in pancreatic cancer cells demonstrated that CAP1 colocalized to the leading edge of lamellipodia with actin. Knockdown of CAP1 by RNA interference resulted in the reduction of lamellipodium formation, motility, and invasion of pancreatic cancer cells. This is the first report demonstrating the overexpression of CAP1 in pancreatic cancers and suggesting the involvement of CAP1 in the aggressive behavior of pancreatic cancer cells. Pancreatic cancer is a leading cause of cancer death worldwide. 1,2 Only about 20% of pancreatic cancer can be surgically resected with curative intent at the time of diagnosis. 3 Mainly due to the difficulty in early detection and frequent metastatic dissemination, the 5-year survival rate for pancreatic cancer patients remains below 5%. 3,4 Considering that vascular involvement, lymph node metastasis, and neural invasion have been proposed as prognostic factors, 5-7 it seems that metastasis is responsible for the aggressive behavior of pancreatic cancer. Pancreatic cancer appears to acquire genetic aberrations with successive alteration of genes involved in the regulation of cell proliferation. The alterations include activating mutations of the KRAS gene 8,9 that occur early in the stage of pancreatic carcinogenesis, and inactivations by the deletion and mutation of the CDKN2A, 10 TP53, 11 and SMAD4 genes. 12 In addition to cell proliferation, cell motility is one of the factors associated with cancer metastasis; however, no alteration of such genes has been revealed in pancreatic cancer. Therefore, alteration of the expression level of genes by epigenetic or transcriptional manner may be a cue to elucidate the mechanism of cancer metastasis.Recent developments in the technology of human genome research enabled us to obtain genome-wide gene-expression profiles, and vast numbers of marker molecule candidates for pancreatic cancer have been proposed. [13][14][15][16][17][18] In this study, xenografts of clinical specimens orthotopically transplanted into severe combined immunodeficient (SCID) mice 19 were utilized as a panel for gene-expression profiling of pancreatic cancer. Among commonly overexpressed genes in pancreatic cancer xenografts, we further evaluated the adenylate cyclaseassociated pr...

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Survival after resection for ductal adenocarcinoma of the pancreas

Cited by 220 publications

References 30 publications

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

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