Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Abiatari, Ivane; DeOliveira, Tiago; Kerkadze, Vachtang; Schwager, Christian; Espósito, Irene; Giese, Nathalia A.; Huber, Peter E.; Bergman, F.; Abdollahi, Amir; Friess, Helmut; Kleeff, Jörg

doi:10.1158/1535-7163.mct-08-0755

Cited by 84 publications

(77 citation statements)

References 27 publications

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“…MAPRE2 up-regulation was evident in the nerve invasive clones of all three pancreatic cancer cell lines (Fig. 1A), confirming our micro-array data (6). Although expression of these genes in all NP clones was not significantly different, the tendency of MAPRE2 up-regulation from NP0 to NP3 was obvious.…”

Section: Resultssupporting

confidence: 85%

“…Previously (6) and in the present study we have identified MAPRE2 as a potential factor in perineural invasion of pancreatic cancer cells. MAPRE2 levels were increased in the three established highly nerve invasive pancreatic cancer cell clones in comparison to the respective parental cells.…”

Section: Discussionsupporting

confidence: 68%

“…As described previously (6), an ex vivo perineural invasion assay was designed using rat vagal nerves and pancreatic cancer cell lines. Three nerve-invasive clones (NP1, 2 and 3) of Panc-1, Colo357 and T3M4 pancreatic cancer cell lines were obtained from these experiments.…”

Section: Resultsmentioning

confidence: 99%

“…MAPRE2 expression was also evident in acinar cells of the normal pancreas, indicating a physiological role in acinar cell function. Interestingly, we have previously shown that KIF14, a member of the kinesin superfamily of microtubule-associated motors that play important roles in intracellular transport and cell division, is as a suppressor of perineural invasion, since loss of KIF14 expression is observed in the majority of neural/ perineural invading cancer cells and since its down-regulation in pancreatic cancer cells results in enhanced perineural invasion (6). The identification of different microtubule associated proteins underscores the importance of this system in perineural invasion, and most likely invasion in general, of pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously identified and described in detail the transcriptome signature of perineural invasion in pancreatic cancer by generating highly nerve invasive pancreatic cancer cells (6). One of the genes that displayed a significant upregulation in pancreatic cancer cells with a high potential for nerve invasion was MAPRE2.…”

Section: Introductionmentioning

confidence: 99%

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The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

Abiatari

Gillen²,

DeOliveira³

et al. 2009

Int J Oncol

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Abstract. Perineural invasion of tumor cells is a characteristic feature of human pancreatic cancer. Unrevealing the molecular mechanisms that enable cancer cells to invade and grow along nerves is important for the development of novel therapeutic strategies in this disease. We have previously identified transcriptional changes in highly nerve invasive pancreatic cancer cells. Here we further analyzed one of the identified deregulated genes, MAPRE2, a microtubule-associated protein.MAPRE2 expression was significantly increased in high versus less nerve invasive pancreatic cancer cells, and changes of MAPRE2 expression resulted in altered actin distribution in these cells. MAPRE2 was predominately expressed in normal pancreatic acinar cells but absent in ductal cells. In pancreatic cancer, there was strong cytoplasmic and occasionally nuclear expression of MAPRE2 in the cancer cells themselves. Increased MAPRE2 mRNA levels in bulk pancreatic cancer tissues tended to be associated with reduced postoperative survival of pancreatic cancer patients. In conclusion, MAPRE2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion. Therefore, targeting this microtubule-associated protein might be a promising approach in the therapy of pancreatic cancer.

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Section: Resultssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

Abiatari

Gillen²,

DeOliveira³

et al. 2009

Int J Oncol

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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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The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

Mukherjee

Wai

et al. 2022

Advanced Biology

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the nerve, is often used synonymously with the term PNI. It is important to differentiate between these two terms as the former can be determined using imaging techniques as it is apparent both clinically and radiologically whereas the latter is more of a histological diagnosis. [4,5] The presence of PNI in malignant neoplasms serves as a marker for poor clinical prognosis and higher mortality rate among patients. PNI is most commonly detected in the aggressive pancreatic, prostate, head and neck, colorectal and gastric cancers. [6] Importantly, in some of these cancers, PNI is the only method of metastasis and it can exist independently without vascular and lymphatic invasion. [2,7] In head and neck, the prevalence of PNI varies between 25-80% when compared to non-PNI cases, whereas in pancreatic cancer, 90% of patients exhibit PNI. [8,9] Furthermore, multiple population-based studies carried out over the years have reported no significant difference in the development of PNI based on age, gender, ethnicity/race or other demographic risk factors like smoking history. [10,11,12] Knowledge of the structure and composition of the nerve and its perineural niche is integral to understanding PNI. The peripheral nerves are primarily composed of Schwann cells, fibroblasts, blood vessels along with axon bundles. The Schwann cells are essential for the maintenance of the axons as well as for the production of myelin in the peripheral nervous system. [13] The innermost endoneurium is composed of the extracellular matrix (ECM), fibroblasts and collagen. It is a delicate layer of connective tissue which wraps around the axon and capillaries. The axons are supported and protected by endoneurial cells which are found in this layer. [14] The perineurium has one or more layers of flat epithelial-like cells which group the axons and endoneurium into fascicles. The presence of tight and adherens junctions (AJs) in the epithelial layer adds to the robustness of this layer thereby providing a permeable, but selective barrier between the surrounding axons and tissues. [15] And finally, the outermost epineurium consists of a dense connective tissue layer composed of elastin fibers and collagen which surround the entire nerve bundle. [16] Numerous blood vessels can also be found in this layer as they serve as the vascular supply to the nerve. Based on the structure of the nerve, Leibig et al. [17] combined past and present definitions and defined PNI as the presence of cancer cells along the nerves Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion.It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which...

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Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

Cited by 84 publications

References 27 publications

The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

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

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

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