Vitamin D receptor agonists to treat diseases involving CXCL12 activity
An agonist, vitamin technology, applied in metabolic diseases, organic active ingredients, respiratory diseases, etc., can solve the problem of unclear cytokines and molecular pathways
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Embodiment 1
[0144] experimental method
[0145] cell line
[0146] The human pancreatic cancer cell lines MiaPaCa-2 (CRL-1420), BxPC-3 (CRL-1687), HPAC (CRL-2119), Pancl (CRL-1469) and AsPCl (CRL-1682) were obtained from ATCC, and Culture according to provider's directions. The mouse pancreatic cancer cell lines p532.1.1, p534.4 and Ink2.2 were derived from PDA in the following mice: LSL-Kras G12D / + ; Trp53 lox / lox ; Pdxl-Cre mice or LSL-Kras G12D ; Ink4a / Arf lox / lox ; Pdxl-Cre mice (Bardeesy et al., 2006; Collisson et al., 2011), and cultured as previously described (Collisson et al., 2011; Collisson et al., 2012). Spontaneously immortalized human pancreatic stellate cell line hPSCs were isolated and established from pancreatic cancer patients after surgical resection as previously described (Mantoni et al., 2011).
[0147] Isolation and Culture of Primary Pancreatic Stellate Cells
[0148] Mouse PSC Isolation
[0149] Pancreatic stellate cells (PSCs) were isolated from the pan...
Embodiment 2
[0215] Identification of cancer-associated gene signatures in PSCs
[0216]To characterize cancer-associated changes in PSCs, massively parallel sequencing (RNA-Seq) of PSC transcriptomes was performed at various stages of activation. Progressive activation of cultured primary PSCs (Omary et al., 2007) is capitalized, and pre-activated (3-day culture) and activated (7-day culture) PSCs isolated from healthy mouse pancreas were analyzed for transcription Group( Figure 1A and Figures 2A to 2C ). This analysis revealed that during activation, PSCs decreased the expression of genes involved in lipid storage and lipid metabolism, consistent with the loss of the lipid droplet phenotype associated with quiescent phase. Activation also results in elevated expression of a range of genes previously associated with tumor supportive potential, including cytokines, growth factors, ECM components and signaling molecules such as Wnts. Concurrent induction of inflammatory genes is of pa...
Embodiment 3
[0219] VDR regulates the PSC activation network
[0220] These analyzes also revealed that PSCs unexpectedly express high levels of the vitamin D receptor (VDR), which was previously thought not to be expressed in the exocrine pancreas (Zeitz et al., 2003)( Figure 1D , 1E , 2D and 2E). VDR expression is maintained in cancer-associated PSCs ( Figure 1F ). Whereas previous work has shown VDR as a key regulator of fibrogenesis gene networks in closely related hepatic stellate cells (Ding et al., 2013), and since l,25(OH) 2 D. 3 This pharmaceutically acceptable receptor was examined for the established anti-inflammatory (Cantorna et al., 1996, 1998; Cantorna et al., 2000; Ma et al., 2006; Nagpal et al., 2005; Deeb et al., 2007) effects of its analogues. Closely related to this study is the strong inverse association of plasma vitamin D levels with pancreatic cancer risk (Wolpin et al., 2012), a relationship that remains unexplained. Furthermore, vitamin D insufficiency has...
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