Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach

Dai, Hong; Li, Rile; Özen, Mustafa; Ittmann, Michael; Anderson, M. Sidney; Wang, Yu; Rowley, David R.; Younes, Mamoun; Ayala, Gustavo

doi:10.1016/j.humpath.2006.08.002

Cited by 88 publications

(90 citation statements)

References 34 publications

(44 reference statements)

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“…According to this theory, the cancer cells within the hypoxic and nutrient-deprived microenvironment grow toward (and along) the nutrient-rich perineural space (8,16). The neurotropism of pancreatic cancer cells is also attributed to the ability of tumor cells to communicate with perineural and/or neural cells over various neuronal-specific molecules and chemoattractants (3,8,17). Although different observations support these concepts, the molecular mechanisms and factors involved in pancreatic cancer cell perineural invasion are not known.…”

Section: Discussionmentioning

confidence: 99%

“…In two other proposed nerve invasion models for pancreatic cancer, in vitro or in vivo mouse environments are used to analyze phenotype-specific changes of nerve-invasive human pancreatic cancer cell lines (3,18). Additionally, these models show significant variability compared with our method, which can be fairly standardized.…”

Section: Discussionmentioning

confidence: 99%

“…PDAC is characterized by a dense tumor stroma (desmoplasia), perineural invasion, and early lymph node and liver metastasis (3,4). Besides systemic spread, perineural invasion is one of the most significant predictors of poor prognosis (3,(5)(6)(7).…”

Section: Introductionmentioning

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%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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%

See 2 more Smart Citations

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Abiatari

DeOliveira

Kerkadze

et al. 2009

Molecular Cancer Therapeutics

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“…23 Furthermore, nerve-cancer interactions during perineural invasion (PNI) results in a survival advantage for cancer cells. 18,19,24,25 These phenomena have been demonstrated in many other cancer types, [26][27][28][29] demonstrating that nerves have a fundamental role in cancer progression. Addressing the functional significance of nerves and identifying the mechanism by which they influence cancer cell growth may lead to therapeutic approaches that target the neural niche in cancer.…”

Section: Introductionmentioning

confidence: 99%

313 Influence of the Neural Microenvironment in Prostate Cancer

Au¹,

Florentin²,

Ding³

et al. 2012

Journal of Urology

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Perineural invasion in pancreatic cancer: proteomic analysis and in vitro modelling

et al. 2019

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Perineural invasion ( PNI ) is a common and characteristic feature of pancreatic ductal adenocarcinoma ( PDAC ) that is associated with poor prognosis, tumor recurrence, and generation of pain. However, the molecular alterations in cancer cells and nerves within PNI have not previously been comprehensively analyzed. Here, we describe our proteomic analysis of the molecular changes underlying neuro‐epithelial interactions in PNI using liquid chromatography–mass spectrometry ( LC ‐ MS / MS ) in microdissected PNI and non‐ PNI cancer, as well as in invaded and noninvaded nerves from formalin‐fixed, paraffin‐embedded PDAC tissues. In addition, an in vitro model of PNI was developed using a co‐culture system comprising PDAC cell lines and PC 12 cells as the neuronal element. The overall proteomic profiles of PNI and non‐ PNI cancer appeared largely similar. In contrast, upon invasion by cancer cells, nerves demonstrated widespread plasticity with a pattern consistent with neuronal injury. The up‐regulation of SCG 2 (secretogranin II ) and neurosecretory protein VGF (nonacronymic) in invaded nerves in PDAC tissues was further validated using immunohistochemistry. The tested PDAC cell lines were found to be able to induce neuronal plasticity in PC 12 cells in our in vitro established co‐culture model. Changes in expression levels of VGF , as well as of two additional proteins previously reported to be overexpressed in PNI , Nestin and Neuromodulin ( GAP 43), closely recapitulated our proteomic findings in PDAC tissues. Furthermore, induction of VGF , while not necessary for PC 12 survival, mediated neurite extension induced by PDAC cell lines. In summary, here we report the proteomic alterations underlying PNI in PDAC and confirm that PDAC cells are able to induce neuronal plasticity. In addition, we describe a novel, simple, and easily adaptable co‐culture model for in vitro study of neuro‐epithelial interactions.

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Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach

Cited by 88 publications

References 34 publications

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

313 Influence of the Neural Microenvironment in Prostate Cancer

Perineural invasion in pancreatic cancer: proteomic analysis and in vitro modelling

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