Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells is necessary for pancreatic cancer cell invasion

Coleman, Stacey J.; Chioni, Athina‐Myrto; Ghallab, Mohammed; Anderson, Rosaleen J.; Lemoine, Nicholas R.; Grose, Richard; Kocher, Hemant M.

doi:10.1016/j.pan.2012.12.032

Cited by 24 publications

(48 citation statements)

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“…The enhanced apoptosis and reduction in proliferation of cancer cells seen in this study may result from a reduction of canonical Wnt signalling in the tumour compartment, as a result of modification in the stromal compartment, by sequestering Wnt ligands, due to sFRP4 secretion . Furthermore, the disrupted fibroblast growth factor (FGF) signalling in the stromal compartment , or targeting of other signalling cascades such as hedgehog, IL6, or CXCL12 , could detrimentally affect the cancer cells by altering the signalling flux of (rather than selectively ablating) key cascades. FGF2/FGFR1 nuclear translocation is vital to activation of PSCs, which is required for cancer progression .…”

Section: Discussionmentioning

confidence: 83%

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma

et al. 2016

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Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti‐tumour efficacy of chemotherapy. Gemcitabine and all‐trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL‐KrasG12D/+;LSL‐Trp53R172H/+;Pdx‐1‐Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial–mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co‐targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour–stroma cross‐talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 83%

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma

et al. 2016

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“…In this review, we have described the translocation of many RTKs into subcellular compartments, especially the nucleus, as holoreceptors or intracellular fragments, and their roles or substrates in non‐canonical RTK signaling, which is much less well‐understood compared with canonical RTK signaling. There is increasing evidence for a role of non‐canonical RTK signaling in disease progression and therapeutic resistance . Thus, more in‐depth investigations of ICD formation as well as nuclear trafficking pathways are required for development of more efficient targeted therapies, as RTK holoreceptors and ICD fragments are not efficiently targeted by current clinically used tyrosine kinase inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Accumulating evidence indicates that at least 12 RTK families contain MRINs that exist either as a holoreceptor or in a truncated form with novel non‐canonical functions in transcriptional regulation, DNA damage and repair, and cell proliferation and invasion . In various cancer types, nuclear RTK expression is associated with poor prognosis . Generally, after ligand‐induced activation, membrane‐bound MRINs are internalized through endocytosis from the cell surface and then transported into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases

Chen

Hung

2015

The FEBS Journal

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Over three quarters of receptor tyrosine kinase (RTK) families are reported to have intracellular localization in response to environmental stimuli. Internalized RTK can bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by γ-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperon or transcription factors while membrane-bound RTKs (full-length or truncated) are transported from the plasma membrane to the endoplasmic reticulum (ER) through the well-established Rab- or clathrin adaptor protein (AP)-coated vesicle retrograde trafficking pathway. Subsequent nuclear transport of membrane-bound RTK can occur via two pathways, INFS and INTERNET, with the former characterized by the release of receptors from ER into the cytosol and the latter by the release of membrane-bound transport from the ER into the nucleoplasm through the inner nuclear membrane. While most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking, and nuclear functions of RTKs and discuss how they promote cancer progression and their clinical implications.

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“…For instance, the stiff mechanical properties of the stroma reduce the perfusion of PDAC tumors and this negatively affects delivery of chemotherapeutics and also oxygen, causing hypoxia. Furthermore, stromal cells have been described to act as chaperones for tumor cells that disseminate from the primary tumor, presumably providing a niche for malignant cells that would otherwise be vulnerable during transit (Coleman et al ., ). In addition, we and others have previously shown that the stroma provides a wide array of ligands that act in trans to support tumor cell growth (Damhofer et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Stromal SPOCK1 supports invasive pancreatic cancer growth

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor‐promoting and tumor‐suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor–stroma interaction in PDAC, there is a need to identify the stromal proteins that are predominantly tumor‐promoting. One possible candidate is SPOCK1 that we previously identified in a screening effort in PDAC. We extensively mined PDAC gene expression datasets, and used species‐specific transcript analysis in mixed‐species models for PDAC to study the patterns and driver mechanisms of SPOCK1 expression in PDAC. Advanced organotypic coculture models with primary patient‐derived tumor cells were used to further characterize the function of this protein. We found SPOCK1 expression to be predominantly stromal. Expression of SPOCK1 was associated with poor disease outcome. Coculture and ligand stimulation experiments revealed that SPOCK1 is expressed in response to tumor cell‐derived transforming growth factor‐beta. Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in PDAC. By defining the expression pattern and functional properties of SPOCK1 in pancreatic cancer, we have identified a stromal mediator of extracellular matrix remodeling that indirectly affects the aggressive behavior of PDAC cells. The recognition that stromal proteins actively contribute to the protumorigenic remodeling of the tumor microenvironment should aid the design of future clinical studies to target specific stromal targets.

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Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells is necessary for pancreatic cancer cell invasion

Cited by 24 publications

References 0 publications

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma

Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases

Stromal SPOCK1 supports invasive pancreatic cancer growth

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