GET THE APP

A Speculative Role for Stromal Gastrin Signaling in Development a
Pancreatic Disorders & Therapy

Pancreatic Disorders & Therapy
Open Access

ISSN: 2165-7092

+44 1478 350008

Review Article - (2013) Volume 0, Issue 0

A Speculative Role for Stromal Gastrin Signaling in Development and Dissemination of Pancreatic Ductal Adenocarcinoma

Gail L Matters1 and Gary A Clawson*
1Department of Biochemistry and Molecular Biology, Hershey Medical Center, Pennsylvania State University, Hershey, PA, USA
2Gittlen Cancer Research Foundation and Departments of Pathology, Biochemistry and Molecular Biology, USA
*Corresponding Author: Gary A Clawson, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, C7768, 500 University Drive, Hershey, PA 17033, USA Email:

Abstract

The peptide growth factor gastrin and its receptor, the G-protein coupled cholecystokinin receptor type B (CCKBR), play an integral role in the growth and progression of pancreatic ductal adenocarcinoma (PDAC). Gastrin immunoreactivity is found in the fetal pancreas but its expression is not detected in normal pancreas after birth, except when it is re-expressed in malignant lesions.

<

Keywords: Gail L Matters and Gary A Clawson

Introduction

The peptide growth factor gastrin and its receptor, the G-protein coupled cholecystokinin receptor type B (CCKBR), play an integral role in the growth and progression of pancreatic ductal adenocarcinoma (PDAC) [1-4]. Gastrin immunoreactivity is found in the fetal pancreas but its expression is not detected in normal pancreas after birth, except when it is re-expressed in malignant lesions [5-8]. Although gastrin is involved physiologically in secretion of gastric acid and growth of the gastrointestinal tract epithelium, it is also an important growth factor for cancers of the pancreas, colon, stomach, and lung, where it stimulates cell growth by an autocrine mechanism [5,7,9-11]. Growth of human PDAC cells in culture or in nude mice can be stimulated by the exogenous addition of gastrin. Blockade of the CCKBR with antagonists, or reduction of gastrinor CCKBR in cancer cells, has been shown to inhibit tumor formation and metastasis, and to promote apoptosis [5,12,13]. However, evidence is also accumulating for paracrine growth effects of gastrin, where for example blockade of CCKBR signaling has been shown to reduce tumor fibrosis and inflammation. CCKBRs have also been identified on cells in the tumor microenvironment, opening the possibility that gastrin signaling in the stromal compartment could have importance in tumor progression and/or dissemination [5,12,14,15]. Here we review the literature on the effects of gastrin:CCKBR signaling on various processes in stroma, and develop the idea that pancreatic stellate cells (PSCs) and tumor infiltrating macrophages (TIMs) may be important players in mediating such effects.

Pleiotropic effects of gastrin and CCKBR receptors on processes involved in tumor invasion

Tumor cell adhesion and migration: Gastrin, acting through the CCKBR, is associated with altered expression of several cell-cell or cell-matrix adhesion molecules [16-18]. In the intestinal epithelial cell line IEC6, gastrin induced a loss of cell-cell adhesion that was mediated by JAK2/PI3K signaling [16]. Activation of JAK2 lead to STAT3 phosphorylation and altered subcellular localization of α- and β- catenins and E-cadherin, with consequent disruption of adherens junctions. In human PANC-1 cells, CCKBR activation by gastrin increased β1 integrin expression at the RNA and protein level and induced tyrosine phosphorylation of β1 integrin through Src and PI3K signaling [17]. The phosphorylation of β1 integrin enhanced adhesion of the cells to fibronectin and laminin. Similarly, gastrin induced a 5-fold increase in βv integrin expression and increased fibronectin adhesion of PANC-1 cells that was βv integrin-mediated [18]. The authors suggested that the gastrin-induced increases in both β1 and βv integrin subunits contribute to alterations in cell-cell adhesion, migration and metastasis [19]. Human gastric cancer cells (AGS) stably over-expressing CCKBR responded to gastrin stimulation with increased MMP-9 secretion and enhanced Matrigel invasion [20].

Stable expression of CCKBR in kidney epithelial (MDCK) cells resulted in a gastrin-mediated increase in cell dissociation, epithelialto- mesenchymal transition (EMT)- like morphological changes, and increased cell motility and invasion through collagen matrices [21]. The role of the CCKBR in cell motility has been further supported by a recent study in PANC-1 cells, where a scratch-wound assay demonstrated that migration was decreased in PANC-1 clones with stably reduced expression of CCKBR [22].

Conversely, several naturally occurring variants of the CCKBR have been identified which possess increased receptor re-sensitization and activity. When these more active CCKBR variants were expressed in human embryonic kidney (HEK293) cells they stimulated cell migration on collagen-coated plates [23]. Analogously, murine fibroblast (NIH 3T3) clones that over-express a constitutively active CCKBR variant also demonstrated increased invasiveness through Matrigel [24]. In vitro invasiveness of both wild-type and variant receptors was enhanced by supplementing the culture media with cholesterol [24], which was suggested to enhance receptor clustering and promote signaling.

Angiogenesis and extravasation: An in vitro angiogenesis model using human umbilical vascular endothelial cells (HuVECs) demonstrated that gastrin can induce HuVEC differentiation and tubule formation to a level comparable to VEGF [25]. This increase in angiogenesis was proposed to occur through the transcriptional activation of heparin-binding epidermal growth factor (HB-EGF) by gastrin [25]. Recent studies using gastric and colon adenocarcinoma cells confirmed that gastrin is transcriptionally up-regulated by hypoxia, independent of Hif, leading to increased secretion of biologically active forms of gastrin by tumor cells [26]. Gastrin’s pro-angiogenic effect was confirmed by Lefranc et al. who also demonstrated that gastrin treatment of HuVECs stimulated release of IL8 and enhanced endothelial cell migration [27]. In functional studies, gastrin induced up-regulation of VAM-1 and P- and E-selectins in HuVECs, and increased “rolling” of peripheral blood mononuclear cells (PBMCs) and their adhesion to HuVECs [28]. These effects were reversed by pretreatment with a CCKBR antagonist, confirming that gastrin signaling through this receptor was essential for the leukocyte-endothelial cell interaction. Although CCK receptors (CCKRs) have been identified on PBMCs [29], these effects of gastrin were confined to endothelial cells, and treatment of isolated leukocytes with gastrin had no functional effect on PBMC/HUVEC interactions.

Metastasis: Only a handful of studies have explored a potential role of gastrin signaling in tumor cell metastasis. Stable reduction of gastrin expression in the human PDAC cell line BxPC-3 resulted in smaller tumors in vivo and a significant reduction in visible metastatic lesions [12]. Others have studied the effects of gastrin neutralization. In one study, gastrin was neutralized by administration of antibodies raised against the 9 amino-terminal amino acids of gastrin linked to diphtheria toxin [30]. Mice implanted with a human colorectal (AP5LV) cell line and treated with the anti-gastrin antibody had smaller primary tumors and fewer pulmonary metastases. Similarly, mice treated with a neutralizing antibody to the N-terminal region of the CCKBR, which encompassed the gastrin binding site, had reduced liver tumor burden after intraperitoneal injection of the human colorectal cancer cell line C170HM2 [31].

Gastrin, cholecystokinin receptors, and the fibrotic tumor microenvironment

The highly fibrotic tumor microenvironment in PDAC is thought to contribute to the widespread chemoresistance in this disease [32]. Highly desmoplastic stroma is evident surrounding even early preneoplastic pancreatic lesions in both humans and mouse PDAC models [33]. Pancreatic stellate cells (PSCs) are the primary source of fibrotic extracellular matrix (ECM) deposits in PDAC, prominently including collagen and fibronectin [34-37]. Indeed, recent work clearly demonstrates that PSCs play critical roles in development and progression of pancreatic cancer [36,38,39].

When activated by growth factors or cytokines, PSCs assume a myofibroblast-like phenotype and secrete collagen and fibronectin [36]. Studies using cultured rat PSCs have shown that these cells express both sub-types of CCKRs, CCKAR and CCKBR, and respond to both cholecystokinin and gastrin stimulation by secreting collagen [15,37]. In fact, cholecystokinin and gastrin each appear to activate rat PSC sin a fashion similar to TGF β, a well-established stellate cell activator. Additionally, antagonism of CCKRs on cultured rat stellate cells in vitro completely blocked collagen production and ECM deposition [15]. Given that gastrin is expressed early in the development of human pancreatic ductal intraepithelial neoplasia (PanIN) [40], and that pancreatic tumor cells secrete biologically active forms of gastrin into the tumor microenvironment [41], PSCs may be responding to gastrin in a paracrine fashion that stimulates desmoplastic responses. Supporting this conjecture, recent studies by our group indicate that blockade of CCKR signaling with a broad-spectrum CCKAR and CCKBR antagonist significantly reduced fibrosis surrounding mPanIN lesions in 8 month old Pdx1-Cre/ LSL-KrasG12D mice, a transgenic model of pancreatic cancer (unpublished data). Additional studies are required to assess the effect of receptor blockade on invasion and metastasis in this model. Another recent study demonstrated that mice that constitutively overexpress gastrin have more myofibroblasts in their colonic epithelium than wild-type mice, and that these myofibroblasts secrete IGF-2 in response to gastrin stimulation [42].

Recent studies have indicated by PSCs have many stem cell characteristics [43], and that PSCs can functionally replace hepatic stellate cells in liver regeneration [43]. Further work has shown that hepatic stellate cells, the functional counterpart to PSCs, directly mediate the differentiation/activation of macrophages [44]; the activated macrophages showed a distinctive IL6-high/IL10-low/TGF β-high pattern and exhibited specific activation of p38 MAPK pathway (see below), a pathway known to be important in macrophage function [45].

There are a number of features of the inflammatory pathways within the PDAC microenvironment which may relate to risk factors for developing PDAC, including obesity and diabetes [46,47]. For example, the M1 macrophage inflammation has been associated with obesity-related insulin resistance [48,49], and there are increased numbers of islet-associated macrophages in type 2 diabetes which appear to be recruited in response to IL8 secretion [50].

Proinflammatory (M1) phenotypic changes may have relevance for obesity as another recognized risk factor for development of PDAC. Obesity has been associated with increased adipose tissue infiltration by macrophages and their polarization to a proinflammatory M1 state [51]. Further studies on adipose tissue macrophages by Lumeng and co-workers [52,53] have also delineated a role for activated macrophages in obesity. Using two obese mouse models – a high fat diet fed mouse model, or a transgenic CCR2-KO mouse model, they found that phenotypic conversion of adipose tissue macrophages from alternatively activated (M2a) to classically activated (M1) phenotype was due to localized recruitment of the inflammatory subtype to macrophage clusters, which was dependent upon C-C motif chemokine receptor 2 (Cccr2), and was not a conversion of resident M2 macrophages to M1 phenotype. Han et al. recently demonstrated that obesity-induced insulin resistance and inflammation is largely dependent upon cJun NH2-terminal kinase (JNK) in M1-polarized macrophages [54].

Circulating Tumor Cells (CTCs) in pancreatic cancer: Influence of Stromal components, and a Speculative Role for Macrophages and Gastrin:CCKBR Signaling in Dissemination of CTCs

As with many other cancers, the prognostic significance of CTCs in pancreatic cancer patients is an area of intense investigation. A number of recent studies have detected CTCs in pancreatic cancer patients using a variety of approaches, including Cell Search and “isolation by size of epithelial tumor cells (ISET) [55], high-definition images [56], and amplification of multiple molecular markers [57-59]. Indeed, it is becoming clear that CTCs in PDAC, as in many other cancers, will have important diagnostic/prognostic significance.

However, there are many caveats which should be mentioned with regard to CTCs. First, the nature of the CTCs actually responsible for development of metastatic lesions (the “bad guys”) is not known. While CTCs have shown prognostic relevance in many cancers, including pancreatic, there is concern that standard approaches to measurement may be compromised. The FDA-approved CellSearch assay (which depends upon identification and counting of EpCAM+/CD45- cells) apparently provides a surrogate measure of the “bad guys”, but problems can arise with it. For example, studies have demonstrated that CTCs may escape EpCAM-based detection due to the epithelialmesenchymal transition [60], often a prominent feature of PDACs, and there are many reports for various types of cancers where EpCAMnegative CTCs have been described (e.g. breast cancer; [61,62]). Specifically with regard to PDAC, Khoja et al. [55] reported that ISET detected CTCs in many more PDAC patients than Cell Search (93% vs. 40%), and also noted that there was marked heterogeneity in staining for various markers used, including pancytokeratin and vimentin, and E-Cadherin. We have also reported isolation of large CTCs from peripheral blood of PDAC patients who were negative for CTCs by Cell Search analysis [63]; these CTCs comprised large cells which coexpressed pancytokeratin markers, the common leukocyte antigen CD45, as well as the macrophage marker CD14 [63].

As further examples, Sergeant et al. [64] observed significant elevations in CTCs in PDAC patients which were induced by surgery, but these elevations were not associated with clinical prognosis after pancreatectomy. Cho et al. [65] have reported CTC aggregates in patients with a variety of carcinomas, including pancreatic, although the significance of such aggregates is not clear at present.

Of particular pertinence to this role, Sergeant et al. [66] developed a gene expression signature for CTCs isolated from PDAC patients, comparing signatures between CTCs, PBMCs, primary tumor, and nontumor pancreatic tissue. They reported that the p38 MAPK pathway showed the highest differential expression in CTCs, prominently including TGFβ [66]. In addition, a group of 9 other genes associated with both the p38MAPK pathway and with cell motility, were also differentially over expressed in CTCs including STAT3 (also involved in gastrin-mediated cell adhesion; [16]). Results indicated that high co-expression of TGFβ and the cell motility panel was an independent predictor of both disease-free and overall survival.

Tissue infiltrating macrophages (TIMs) may not only have pleiotropic effects on PDACs and pancreatic stroma, but may in addition actively participate in dissemination of PDACs. TIMs have been shown to be important players in pancreatic cancer [67]. Targeting TIMs, via inhibition of the Cccr2 receptor (or colony-stimulating factor-1 receptor), decreased the number of tumor initiating cells in PDACs, inhibited metastases, and increased antitumor T-cell responses. Conversely, TIMs were also shown to directly enhance the tumor-initiating cells of PDACs by activating STAT3, facilitating macrophage-mediated suppression of CD8+ T lymphocytes [67].

Summary

We hypothesize that stromal cells in the inflammatory tumor microenvironment of PDACs are important players in the dissemination of PDAC cells, via actions of gastrin and the CCKBR. Gastrin activates PSCs, which in turn activate macrophages. A subset of these macrophages appear to also express CCKBR, and we routinely observe large, epithelioid cells, as well as acute/chronic inflammatory cells and PSCs in focal areas in the immediate vicinity of ductal epithelium (Figure 1), suggesting the working hypothesis that the large epithelioid CCKBR+ cells represent activated TIMs. Such activated macrophages, with active signaling of the p38MAPK and TGFβ pathways, seem to actually fuse with tumor cells, and could thus confer the phenotype for PDAC CTCs described by Sergeant et al. [66] and account for our findings [63]. In fact, this fusion process has long been proposed as a unifying concept for the basis of metastases by Pawelek and co-workers [68-70], a process which is eminently consistent with the literature on TIMs and CTCs in PDAC.

pancreatic-disorders-therapy-occasional-light

Figure 1: Stromal periductal CCKBR immunoreactivity in PDAC. Immunohistochemical staining for the CCKBR was done using 6-μm sections from formalin-fixed paraffin-embedded tissues (all samples were obtained under the auspices of IRB-approved protocols). Slides were deparaffinized in xylene followed by successive ethanol washes and rehydration. Immunohistochemical staining was performed following the manufacturer’s protocol (Vector Laboratories, kit #SP-2001). Blocking was in 1% normal rabbit serum in TBS, followed by incubations with an Avidin D solution and then a biotin solution. Primary CCKBR antibody (#77077, AbCam) was used at a 1:200 dilution, followed by a secondary anti-goat antibody. Slides were then incubated in Vectastain Elite ABC reagent, and then in ImmPACT DAB chromagen solution until color developed. Slides were counter stained with hematoxylin. Representative photos from PDAC samples are shown (20X). The upper and lower right panels show representative, bizarre epithelioid cells at higher power (40X). In many cases, these large cells show extensions into the stromal and ductal compartments (similar to stellate cells), or appear to have fused with or phagocytosed adjacent cells. Aside from focal periductal staining, most regions of fibrous stroma were negative for CCKBR expression (see upper left panel for example). We also noted occasional light focal staining for CCKAR (not shown).

Acknowledgements

This work was supported by grant funds from the V Foundation for Cancer Research. We thank Qing Zhong in Comparative Medicine for assistance with immunohistochemical staining, and Chris McGovern for helpful comments. This article is funded by NIH grant number is CA137595 to GAC.

References

  1. Berna MJ, Jensen RT (2007) Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr Top Med Chem 7: 1211-1231.
  2. Dufresne M, Seva C, Fourmy D (2006) Cholecystokinin and gastrin receptors. Physiol Rev 86: 805-847.
  3. Grabowska AM, Watson SA (2007) Role of gastrin peptides in carcinogenesis. Cancer Lett 257: 1-15.
  4. Rozengurt E, Walsh JH (2001) Gastrin, CCK, signaling, and cancer. Annu Rev Physiol 63: 49-76.
  5. Harris JC, Gilliam AD, McKenzie AJ, Evans SA, Grabowska AM, et al. (2004) The biological and therapeutic importance of gastrin gene expression in pancreatic adenocarcinomas. Cancer Res 64: 5624-5631.
  6. Smith JP, Fantaskey AP, Liu G, Zagon IS (1995) Identification of gastrin as a growth peptide in human pancreatic cancer. Am J Physiol 268: R135-141.
  7. Smith JP, Shih A, Wu Y, McLaughlin PJ, Zagon IS (1996) Gastrin regulates growth of human pancreatic cancer in a tonic and autocrine fashion. Am J Physiol 270: R1078-1084.
  8. Weinberg DS, Ruggeri B, Barber MT, Biswas S, Miknyocki S, et al. (1997) Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. J Clin Invest 100: 597-603.
  9. Ferrand A, Wang TC (2006) Gastrin and cancer: a review. Cancer Lett 238: 15-29.
  10. Rehfeld JF, Bardram L, Hilsted L (1989) Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin. Cancer Res 49: 2840-2843.
  11. Smith JP, Solomon TE (1988) Effects of gastrin, proglumide, and somatostatin on growth of human colon cancer. Gastroenterology 95: 1541-1548.
  12. Matters GL, Harms JF, McGovern CO, Jayakumar C, Crepin K, et al. (2009) Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas 38: e151-161.
  13. Jin G, Ramanathan V, Quante M, Baik GH, Yang X, et al. (2009) Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J Clin Invest 119: 2691-2701.
  14. Phillips PA, Yang L, Shulkes A, Vonlaufen A, Poljak A, et al. (2010) Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic exocrine secretion. Proc Natl Acad Sci U S A 107: 17397-17402.
  15. Berna MJ, Seiz O, Nast JF, Benten D, Bläker M, et al. (2010) CCK1 and CCK2 receptors are expressed on pancreatic stellate cells and induce collagen production. J Biol Chem 285: 38905-38914.
  16. Ferrand A, Kowalski-Chauvel A, Bertrand C, Pradayrol L, Fourmy D, et al. (2004) Involvement of JAK2 upstream of the PI 3-kinase in cell-cell adhesion regulation by gastrin. Exp Cell Res 301: 128-138.
  17. Cayrol C, Clerc P, Bertrand C, Gigoux V, Portolan G, et al. (2006) Cholecystokinin-2 receptor modulates cell adhesion through beta 1-integrin in human pancreatic cancer cells. Oncogene 25: 4421-4428.
  18. Cayrol C, Bertrand C, Kowalski-Chauvel A, Daulhac L, Cohen-Jonathan-Moyal E, et al. (2011) av integrin: a new gastrin target in human pancreatic cancer cells. World J Gastroenterol 17: 4488-4495.
  19. Guo W, Giancotti FG (2004) Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5: 816-826.
  20. Wroblewski LE, Pritchard DM, Carter S, Varro A (2002) Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. Biochem J 365: 873-879.
  21. Bierkamp C, Kowalski-Chauvel A, Dehez S, Fourmy D, Pradayrol L, et al. (2002) Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Oncogene 21: 7656-7670.
  22. Fino KK, Matters GL, McGovern CO, Gilius EL, Smith JP (2012) Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. Am J Physiol Gastrointest Liver Physiol 302: G1244-1252.
  23. Willard MD, Lajiness ME, Wulur IH, Feng B, Swearingen ML, et al. (2012) Somatic mutations in CCK2R alter receptor activity that promote oncogenic phenotypes. Mol Cancer Res 10: 739-749.
  24. Paillasse MR, de Medina P, Amouroux G, Mhamdi L, Poirot M, et al. (2009) Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion. J Lipid Res 50: 2203-2211.
  25. Clarke PA, Dickson JH, Harris JC, Grabowska A, Watson SA (2006) Gastrin enhances the angiogenic potential of endothelial cells via modulation of heparin-binding epidermal-like growth factor. Cancer Res 66: 3504-3512.
  26. Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, et al. (2012) Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF). Endocrinology 153: 3006-3016.
  27. Lefranc F, Mijatovic T, Mathieu V, Rorive S, Decaestecker C, et al. (2004) Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells. Clin Cancer Res 10: 8250-8265.
  28. Ibiza S, Alvarez A, Romero W, Barrachina MD, Esplugues JV, et al. (2009) Gastrin induces the interaction between human mononuclear leukocytes and endothelial cells through the endothelial expression of P-selectin and VCAM-1. Am J Physiol Cell Physiol 297: C1588-1595.
  29. Schmitz F, Schrader H, Otte J, Schmitz H, Stüber E, et al. (2001) Identification of CCK-B/gastrin receptor splice variants in human peripheral blood mononuclear cells. Regul Pept 101: 25-33.
  30. Watson SA, Michaeli D, Morris TM, Clarke P, Varro A, et al. (1999) Antibodies raised by gastrimmune inhibit the spontaneous metastasis of a human colorectal tumour, AP5LV. Eur J Cancer 35: 1286-1291.
  31. Watson SA, Clarke PA, Morris TM, Caplin ME (2000) Antiserum raised against an epitope of the cholecystokinin B/gastrin receptor inhibits hepatic invasion of a human colon tumor. Cancer Res 60: 5902-5907.
  32. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6: 583-592.
  33. Korc M (2007) Pancreatic cancer-associated stroma production. Am J Surg 194: S84-86.
  34. Omary MB, Lugea A, Lowe AW, Pandol SJ (2007) The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117: 50-59.
  35. Neesse A, Michl P, Frese KK, Feig C, Cook N, et al. (2011) Stromal biology and therapy in pancreatic cancer. Gut 60: 861-868.
  36. Apte MV, Pirola RC, Wilson JS (2012) Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 3: 344.
  37. Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, et al. (2012) StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61: 172-178.
  38. Masamune A, Hamada S, Kikuta K, Takikawa T, Miura S, et al. (2013) The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice. Scand J Gastroenterol.
  39. Tod J, Jenei V, Thomas G, Fine D (2013) Tumor-stromal interactions in pancreatic cancer. Pancreatology 13: 1-7.
  40. Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, et al. (2005) Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 65: 1619-1626.
  41. Goetze JP, Nielsen FC, Burcharth F, Rehfeld JF (2000) Closing the gastrin loop in pancreatic carcinoma: coexpression of gastrin and its receptor in solid human pancreatic adenocarcinoma. Cancer 88: 2487-2494.
  42. Duckworth CA, Clyde D, Worthley DL, Wang TC, Varro A, et al. (2013) Progastrin-Induced Secretion of Insulin-Like Growth Factor-2 from Colonic Myofibroblasts Stimulates Colonic Epithelial Proliferation in Mice. Gastroenterology.
  43. Kordes C, Sawitza I, Götze S, Häussinger D (2012) Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 7: e51878.
  44. Chang J, Hisamatsu T, Shimamura K, Yoneno K, Adachi M, et al. (2012) Activated hepatic stellate cells mediate the differentiation of macrophages. Hepatol Res.
  45. Hall JP, Davis RJ (2002) Inhibition of the p38 pathway upregulates macrophage JNK and ERK activities, and the ERK, JNK, and p38 MAP kinase pathways are reprogrammed during differentiation of the murine myeloid M1 cell line. J Cell Biochem 86: 1-11.
  46. Bracci PM (2012) Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog 51: 53-63.
  47. Roberts DL, Dive C, Renehan AG (2010) Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 61: 301-316.
  48. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, et al. (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447: 1116-1120.
  49. Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, et al. (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8: 301-309.
  50. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, et al. (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56: 2356-2370.
  51. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796-1808.
  52. Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175-184.
  53. Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57: 3239-3246.
  54. Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, et al. (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339: 218-222.
  55. Khoja L, Backen A, Sloane R, Menasce L, Ryder D, et al. (2012) A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer 106: 508-516.
  56. Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, et al. (2012) Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 9: 016003.
  57. de Albuquerque A, Kubisch I, Ernst D, Breier G, Stamminger G, et al. (2012) Development of a molecular multimarker assay for the analysis of circulating tumor cells in adenocarcinoma patients. Clin Lab 58: 373-384.
  58. de Albuguerque A, Kubisch I, Breier G, Stamminger G, Fersis N, et al. (2012) Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology 82: 3-10.
  59. Cen P, Ni X, Yang J, Graham DY, Li M (2012) Circulating tumor cells in the diagnosis and management of pancreatic cancer. Biochim Biophys Acta 1826: 350-356.
  60. Gorges TM, Tinhofer I, Drosch M, Röse L, Zollner TM, et al. (2012) Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer 12: 178.
  61. Königsberg R, Obermayr E, Bises G, Pfeiler G, Gneist M, et al. (2011) Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol 50: 700-710.
  62. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, et al. (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101: 61-66.
  63. Clawson GA, Kimchi E, Patrick SD, Xin P, Harouaka R, et al. (2012) Circulating tumor cells in melanoma patients. PLoS One 7: e41052.
  64. Sergeant G, Roskams T, van Pelt J, Houtmeyers F, Aerts R, et al. (2011) Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma. BMC Cancer 11: 47.
  65. Cho EH, Wendel M, Luttgen M, Yoshioka C, Marrinucci D, et al. (2012) Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys Biol 9: 016001.
  66. Sergeant G, van Eijsden R, Roskams T, Van Duppen V, Topal B (2012) Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery. BMC Cancer 12: 527.
  67. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, et al. (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73: 1128-1141.
  68. Pawelek JM, Chakraborty AK (2008) The cancer cell--leukocyte fusion theory of metastasis. Adv Cancer Res 101: 397-444.
  69. Pawelek JM, Chakraborty AK (2008) Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8: 377-386.
  70. Rachkovsky M, Sodi S, Chakraborty A, Avissar Y, Bolognia J, et al. (1998) Melanoma x macrophage hybrids with enhanced metastatic potential. Clin Exp Metastasis 16: 299-312.
Citation: Matters GL, Clawson GA (2013) A Speculative Role for Stromal Gastrin Signaling in Development and Dissemination of Pancreatic Ductal Adenocarcinoma.Pancreatic Dis Ther S4:003.

Copyright: © 2013 Matters GL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top