EDITORIALS activation and biological effects of TGF-beta. Biochim Biophys Acta 2009;1793:1165–1173. 21. Paoloni-Giacobino A, Rossier C, Papasavvas MP, et al. Frequency of replication/transcription errors in (A)/(T) runs of human genes. Hum Genet 2001;109:40–47.
Funding Support for this work was provided by the NIH (P30CA15704, UO1CA152756), and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (W.M.G.).
Reprint requests Address requests for reprints to: William M. Grady, 1100 Fairview Avenue North D4-100, Seattle, Washington 98109. e-mail: [email protected].
© 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.023
Conflicts of interest The author discloses no conflicts.
Somatostatin Receptor Subtype 2 as Pancreatic Tumorigenesis Suppressor: Identification of a New Targetable Signaling Node See “Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16,” by Chalabi-Dchar M, Cassant-Sourdy S, and Duluc C et al, on page 1452.
P
ancreatic ductal adenocarcinoma (PDA) remains a devastating disease, with minimal progress being made in effectively treating this cancer over the last 40 years. With the advent of PDA genetically engineered mouse models (GEMMs) a decade ago,1 tremendous progress has been made in understanding how pancreatic neoplasia forms, behaves, and progresses, revealing aspects of the unique biology that potentially influences the behavior of the invasive and metastatic cancers. The recent discovery that ductal neoplasia in these GEMMs likely arises from acinar cells2,3 after transdifferentiation to a ductal phenotype implicates a striking plasticity of differentiation status programmed into the neoplastic pancreas from its earliest stages. This plasticity possibly manifests at later stages, including invasive behavior before obvious progression to carcinoma.4 In light of the acinar cell origin of neoplasia in PDA GEMMs, perhaps it is not surprising that factors that maintain acinar cell differentiation act as tumorigenesis suppressors, requiring their loss or severe down-regulation during tumor initiation.5–7 Likewise, given that the Kras oncogene is the most commonly mutated oncogene in PDA, and is the primary genetic driver of the PDA models, it was somewhat foreseeable that pathways downstream of Kras signaling would be involved in the acinar-to-ductal transdifferentiation process that is the initial step in tumorigenesis (Figure 1). Indeed, inhibition of mitogen-activated protein kinase kinase (also known as MEK) blocks acinar transdifferentiation in vitro8–10 and in vivo9,10 and can reinforce acinar differentiation in early pancreatic intraepithelial neoplasia (PanIN) lesions in vivo.10 Similarly, ablation of PI3K activity effectively blocks pancreas tumor formation by affecting stable transdifferentiation.11,12 Interestingly, these pathways also seem to be critical in the pathology of chronic pancreatitis,9,12 a risk factor for PDA that may also represent a point of intervention in chemoprevention strategies.
Acinar cell transdifferentiation induced by oncogenic Kras is inefficient in vivo as evidenced by the common PDA GEMMs in which mutant Kras expression is initiated at organogenesis, yet the pancreas develops normally.1 Indeed, neoplasia is not observed in these pancreata until the mice are several weeks of age, with the majority of the tissue still appearing histologically normal and functional.1 From this we can speculate that there are likely several mechanisms inherent to the normal pancreas that dampens the effectiveness of Kras-induced transdifferentiation and transformation. These mechanisms are likely to include the aforementioned factors directly involved in maintaining acinar cell differentiation and others that reinforce acinar cell identity by antagonizing Kras signaling to its downstream effectors. In this issue of Gastroenterology, Chalabi-Dchar et al13 identify the G-protein–coupled receptor, somatostatin receptor subtype 2 (SST2), as a powerful antagonist to Kras signaling to PI3K, thus greatly limiting pancreas tumorigenesis in a KrasG12D expressing GEMM. SST2 is found to be expressed exclusively in acinar cells and, when genetically reduced (using heterozygous conditional knockout mice) or entirely ablated, KrasG12D-induced tumor formation is greatly accelerated, ultimately leading to more cancer formation within greatly reduced lifespan of the mice. Because SST2 expression decreases during PanIN progression to PDA, the increased incidence of cancer is likely to be primarily a consequence of earlier and more widespread tumor initiation. Consistent with this, by treating the SST2 wildtype KrasG12D mice with octreotide, an SST2 agonist, the authors were able to limit substantially the degree of tumorigenesis. As in the mouse model, SST2 expression is lost in human PDA, eliminating it as a potential drug target to slow or reverse the progression of pancreatic cancer after it has formed. However, its limited expression in early PanIN and ductal metaplasia suggests that ligand stimulation may be used to reinforce acinar differentiation in atrisk patients, such as those with chronic pancreatitis. Digging deeper into the mechanism of SST2 inhibition of tumorigenesis, the authors find that ablation of SST2 from KrasG12D-expressing acinar cells leads to a greater amount of active Ras protein and a concomitantly high level of pAKT, a PI3K downstream effector. Curiously, despite its effect on Ras, SST ablation did not affect MEK/ERK activity, which is generally considered a reliable indicator of Ras 1279
EDITORIALS Figure 1. A multistep model of pancreatic tumorigenesis, including acinar-toductal transdifferentiation and subsequent transformation to neoplasia (PanIN). In this issue of Gastroenterology, ChalabiDchar et al13 demonstrate that Somatostatin Receptor Subtype 2 (SST2) and CXCL16/CXCR6 join a host of other effectors that block (red line) and promote (blue arrow) the transdifferentiation step of tumorigenesis, respectively.
signaling. Exploring further downstream signals, they find high levels of active nuclear factor kB in the SST2-ablated pancreata, which suggested an enhanced proinflammatory circuit, confirmed by high levels of cyclooxygenase-2 and interleukin-6 expression, both of which are known to enhance pancreatic tumorigenesis and progression,14,15 together with the cytokine CXCL16 and its receptor CXCR6. Previous in vitro studies from this research group have shown that SST2 inhibits PI3K signaling by directly interacting with the PI3K p85 regulatory subunit,16 and the current study adds that blocking CXCL16/CXCR6 signaling abrogates the bulk of the increase in PI3K/AKT/nuclear factor kB induced by pancreatic SST2 loss. Indeed, blocking CXCL16 in vivo in the both SST2 intact and ablated models reduced tumor formation, eliminating most of the tumorpromoting effect of SST2 ablation. Previous studies in PDA and other cancer cell lines also reveal pro-invasion activities of the CXCL16/CXCR6 circuit.17 Although not tested in the current study, CXCL16/CXCR6 seems to be an attractive therapeutic target for cancer treatment because it, unlike SST2, remains elevated in mouse and human PDA. Targeting CXCL16/CXCR6 is likely to have additional benefits beyond the elimination of autocrine loop in PDA tumor cells. The CXCL16 ligand is expressed by multiple cell types, such as lymphocytes, dendritic cells, and B-cells,17 with stromal expression confirmed in PDA samples by the authors of the current study. This suggests that CXCR6 on tumor cells may be activated via paracrine signaling from the microenvironment as well as through autocrine signaling. Additionally, CXCL16/CXCR6 signaling promotes inflammation, including macrophage and T-cell infiltration,17 both of which have been shown to contribute to pancreatic tumor formation.18 Therefore, CXCL16 joins cytokines like macrophage-derived tumor necrosis factor-a,18 stellate and immune cell-derived interleukin (IL)-614 and T helper 17 Tcell–derived IL-1719 as a pancreas tumor-promoting cytokine and its inhibition may limit the influx of stromal cells that deliver additional tumor-promoting factors. Many targetable signaling circuits have been shown to be activated in, and critical for, pancreatic tumorigenesis in PDA GEMMs over the past several years. These include receptor tyrosine kinases (such as the epidermal growth 1280
factor receptor9,20), Kras downstream effectors (such as MEK10 and PI3K11,12), and the cytokines mentioned. In GEMMs, inhibition or ablation of each of these effectors individually is sufficient to block tumorigenesis or tumor progression and, in some cases, can induce regression of early neoplasms.9,10 Yet, in the clinical setting, targeting these pathways has proven minimally effective when combined with the current standard of care. This disconnect is likely a result of experimental designs to interrupt these pathways before the tumors have formed at all or in relatively homogeneous early PanINs, as opposed to the genetic and environmental heterogeneity that exists in a cancer that likely formed several years prior. Drug resistance in this context is common, possibly because of the differentiation plasticity of the cancer cells or resistant subclones selected for within the considerable cellular heterogeneity. Thus, at least for targeted therapy, drug combinations will be a likely necessity. With the work of Chalabi-Dchar et al, not only do we learn the role of SST2 as a novel pancreatic tumorigenesis suppressor, they also identify CXCL16/CXCR6 inhibitors as possible additions to the therapeutic arsenal when mounting a multifarious assault against this devastating disease. HOWARD C. CRAWFORD Departments of Molecular & Integrative Physiology and Internal Medicine University of Michigan Ann Arbor, Michigan
References 1. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437–450. 2. Ray KC, Bell KM, Yan J, et al. Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLoS One 2011;6:e16786. 3. Kopp JL, von Figura G, Mayes E, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:737–750.
EDITORIALS 4. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148:349–361. 5. Martinelli P, Madriles F, Canamero M, et al. The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut 2015 Jan 16 [Epub ahead of print]. 6. von Figura G, Morris JP, Wright CV, et al. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 2014; 63:656–664. 7. Shi G, Zhu L, Sun Y, et al. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 2009;136:1368–1378. 8. Shi G, DiRenzo D, Qu C, et al. Maintenance of acinar cell organization is critical to preventing Krasinduced acinar-ductal metaplasia. Oncogene 2013;32: 1950–1958. 9. Ardito CM, Gruner BM, Takeuchi KK, et al. EGF Receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012;22:304–317. 10. Collins MA, Yan W, Sebolt-Leopold JS, et al. Mapk signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 2014;146:822–834.e7. 11. Wu CY, Carpenter ES, Takeuchi KK, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 2014; 147:1405–1416 e7. 12. Baer R, Cintas C, Dufresne M, et al. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. Genes Dev 2014;28:2621–2635. 13. Chalabi-Dchar M, Cassant-Sourdy S, Duluc C, et al. Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16. Gastroenterology 2015;148:1452–1465.
14. Zhang Y, Yan W, Collins MA, et al. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res 2013;73:6359–6374. 15. Funahashi H, Satake M, Dawson D, et al. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res 2007;67: 7068–7071. 16. Bousquet C, Guillermet-Guibert J, Saint-Laurent N, et al. Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. EMBO J 2006;25:3943–3954. 17. Deng L, Chen N, Li Y, et al. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim Biophys Acta 2010;1806:42–49. 18. Liou GY, Doppler H, Necela B, et al. Macrophagesecreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. J Cell Biol 2013;202:563–577. 19. McAllister F, Bailey JM, Alsina J, et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 2014;25:621–637. 20. Navas C, Hernandez-Porras I, Schuhmacher AJ, et al. EGF receptor signaling is essential for k-ras oncogenedriven pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:318–330. Reprint requests Address requests for reprints to: Howard C. Crawford, Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, NCRC Bldg 520, Room 1347, 1600 Huron Parkway Ann Arbor, Michigan. 48109-1600. e-mail: [email protected].
Conflicts of interest The author discloses no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.025
1281
Funding Support for this work was provided by the NIH (P30CA15704, UO1CA152756), and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (W.M.G.).
Reprint requests Address requests for reprints to: William M. Grady, 1100 Fairview Avenue North D4-100, Seattle, Washington 98109. e-mail: [email protected].
© 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.023
Conflicts of interest The author discloses no conflicts.
Somatostatin Receptor Subtype 2 as Pancreatic Tumorigenesis Suppressor: Identification of a New Targetable Signaling Node See “Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16,” by Chalabi-Dchar M, Cassant-Sourdy S, and Duluc C et al, on page 1452.
P
ancreatic ductal adenocarcinoma (PDA) remains a devastating disease, with minimal progress being made in effectively treating this cancer over the last 40 years. With the advent of PDA genetically engineered mouse models (GEMMs) a decade ago,1 tremendous progress has been made in understanding how pancreatic neoplasia forms, behaves, and progresses, revealing aspects of the unique biology that potentially influences the behavior of the invasive and metastatic cancers. The recent discovery that ductal neoplasia in these GEMMs likely arises from acinar cells2,3 after transdifferentiation to a ductal phenotype implicates a striking plasticity of differentiation status programmed into the neoplastic pancreas from its earliest stages. This plasticity possibly manifests at later stages, including invasive behavior before obvious progression to carcinoma.4 In light of the acinar cell origin of neoplasia in PDA GEMMs, perhaps it is not surprising that factors that maintain acinar cell differentiation act as tumorigenesis suppressors, requiring their loss or severe down-regulation during tumor initiation.5–7 Likewise, given that the Kras oncogene is the most commonly mutated oncogene in PDA, and is the primary genetic driver of the PDA models, it was somewhat foreseeable that pathways downstream of Kras signaling would be involved in the acinar-to-ductal transdifferentiation process that is the initial step in tumorigenesis (Figure 1). Indeed, inhibition of mitogen-activated protein kinase kinase (also known as MEK) blocks acinar transdifferentiation in vitro8–10 and in vivo9,10 and can reinforce acinar differentiation in early pancreatic intraepithelial neoplasia (PanIN) lesions in vivo.10 Similarly, ablation of PI3K activity effectively blocks pancreas tumor formation by affecting stable transdifferentiation.11,12 Interestingly, these pathways also seem to be critical in the pathology of chronic pancreatitis,9,12 a risk factor for PDA that may also represent a point of intervention in chemoprevention strategies.
Acinar cell transdifferentiation induced by oncogenic Kras is inefficient in vivo as evidenced by the common PDA GEMMs in which mutant Kras expression is initiated at organogenesis, yet the pancreas develops normally.1 Indeed, neoplasia is not observed in these pancreata until the mice are several weeks of age, with the majority of the tissue still appearing histologically normal and functional.1 From this we can speculate that there are likely several mechanisms inherent to the normal pancreas that dampens the effectiveness of Kras-induced transdifferentiation and transformation. These mechanisms are likely to include the aforementioned factors directly involved in maintaining acinar cell differentiation and others that reinforce acinar cell identity by antagonizing Kras signaling to its downstream effectors. In this issue of Gastroenterology, Chalabi-Dchar et al13 identify the G-protein–coupled receptor, somatostatin receptor subtype 2 (SST2), as a powerful antagonist to Kras signaling to PI3K, thus greatly limiting pancreas tumorigenesis in a KrasG12D expressing GEMM. SST2 is found to be expressed exclusively in acinar cells and, when genetically reduced (using heterozygous conditional knockout mice) or entirely ablated, KrasG12D-induced tumor formation is greatly accelerated, ultimately leading to more cancer formation within greatly reduced lifespan of the mice. Because SST2 expression decreases during PanIN progression to PDA, the increased incidence of cancer is likely to be primarily a consequence of earlier and more widespread tumor initiation. Consistent with this, by treating the SST2 wildtype KrasG12D mice with octreotide, an SST2 agonist, the authors were able to limit substantially the degree of tumorigenesis. As in the mouse model, SST2 expression is lost in human PDA, eliminating it as a potential drug target to slow or reverse the progression of pancreatic cancer after it has formed. However, its limited expression in early PanIN and ductal metaplasia suggests that ligand stimulation may be used to reinforce acinar differentiation in atrisk patients, such as those with chronic pancreatitis. Digging deeper into the mechanism of SST2 inhibition of tumorigenesis, the authors find that ablation of SST2 from KrasG12D-expressing acinar cells leads to a greater amount of active Ras protein and a concomitantly high level of pAKT, a PI3K downstream effector. Curiously, despite its effect on Ras, SST ablation did not affect MEK/ERK activity, which is generally considered a reliable indicator of Ras 1279
EDITORIALS Figure 1. A multistep model of pancreatic tumorigenesis, including acinar-toductal transdifferentiation and subsequent transformation to neoplasia (PanIN). In this issue of Gastroenterology, ChalabiDchar et al13 demonstrate that Somatostatin Receptor Subtype 2 (SST2) and CXCL16/CXCR6 join a host of other effectors that block (red line) and promote (blue arrow) the transdifferentiation step of tumorigenesis, respectively.
signaling. Exploring further downstream signals, they find high levels of active nuclear factor kB in the SST2-ablated pancreata, which suggested an enhanced proinflammatory circuit, confirmed by high levels of cyclooxygenase-2 and interleukin-6 expression, both of which are known to enhance pancreatic tumorigenesis and progression,14,15 together with the cytokine CXCL16 and its receptor CXCR6. Previous in vitro studies from this research group have shown that SST2 inhibits PI3K signaling by directly interacting with the PI3K p85 regulatory subunit,16 and the current study adds that blocking CXCL16/CXCR6 signaling abrogates the bulk of the increase in PI3K/AKT/nuclear factor kB induced by pancreatic SST2 loss. Indeed, blocking CXCL16 in vivo in the both SST2 intact and ablated models reduced tumor formation, eliminating most of the tumorpromoting effect of SST2 ablation. Previous studies in PDA and other cancer cell lines also reveal pro-invasion activities of the CXCL16/CXCR6 circuit.17 Although not tested in the current study, CXCL16/CXCR6 seems to be an attractive therapeutic target for cancer treatment because it, unlike SST2, remains elevated in mouse and human PDA. Targeting CXCL16/CXCR6 is likely to have additional benefits beyond the elimination of autocrine loop in PDA tumor cells. The CXCL16 ligand is expressed by multiple cell types, such as lymphocytes, dendritic cells, and B-cells,17 with stromal expression confirmed in PDA samples by the authors of the current study. This suggests that CXCR6 on tumor cells may be activated via paracrine signaling from the microenvironment as well as through autocrine signaling. Additionally, CXCL16/CXCR6 signaling promotes inflammation, including macrophage and T-cell infiltration,17 both of which have been shown to contribute to pancreatic tumor formation.18 Therefore, CXCL16 joins cytokines like macrophage-derived tumor necrosis factor-a,18 stellate and immune cell-derived interleukin (IL)-614 and T helper 17 Tcell–derived IL-1719 as a pancreas tumor-promoting cytokine and its inhibition may limit the influx of stromal cells that deliver additional tumor-promoting factors. Many targetable signaling circuits have been shown to be activated in, and critical for, pancreatic tumorigenesis in PDA GEMMs over the past several years. These include receptor tyrosine kinases (such as the epidermal growth 1280
factor receptor9,20), Kras downstream effectors (such as MEK10 and PI3K11,12), and the cytokines mentioned. In GEMMs, inhibition or ablation of each of these effectors individually is sufficient to block tumorigenesis or tumor progression and, in some cases, can induce regression of early neoplasms.9,10 Yet, in the clinical setting, targeting these pathways has proven minimally effective when combined with the current standard of care. This disconnect is likely a result of experimental designs to interrupt these pathways before the tumors have formed at all or in relatively homogeneous early PanINs, as opposed to the genetic and environmental heterogeneity that exists in a cancer that likely formed several years prior. Drug resistance in this context is common, possibly because of the differentiation plasticity of the cancer cells or resistant subclones selected for within the considerable cellular heterogeneity. Thus, at least for targeted therapy, drug combinations will be a likely necessity. With the work of Chalabi-Dchar et al, not only do we learn the role of SST2 as a novel pancreatic tumorigenesis suppressor, they also identify CXCL16/CXCR6 inhibitors as possible additions to the therapeutic arsenal when mounting a multifarious assault against this devastating disease. HOWARD C. CRAWFORD Departments of Molecular & Integrative Physiology and Internal Medicine University of Michigan Ann Arbor, Michigan
References 1. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437–450. 2. Ray KC, Bell KM, Yan J, et al. Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLoS One 2011;6:e16786. 3. Kopp JL, von Figura G, Mayes E, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:737–750.
EDITORIALS 4. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148:349–361. 5. Martinelli P, Madriles F, Canamero M, et al. The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut 2015 Jan 16 [Epub ahead of print]. 6. von Figura G, Morris JP, Wright CV, et al. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 2014; 63:656–664. 7. Shi G, Zhu L, Sun Y, et al. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 2009;136:1368–1378. 8. Shi G, DiRenzo D, Qu C, et al. Maintenance of acinar cell organization is critical to preventing Krasinduced acinar-ductal metaplasia. Oncogene 2013;32: 1950–1958. 9. Ardito CM, Gruner BM, Takeuchi KK, et al. EGF Receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012;22:304–317. 10. Collins MA, Yan W, Sebolt-Leopold JS, et al. Mapk signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 2014;146:822–834.e7. 11. Wu CY, Carpenter ES, Takeuchi KK, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 2014; 147:1405–1416 e7. 12. Baer R, Cintas C, Dufresne M, et al. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. Genes Dev 2014;28:2621–2635. 13. Chalabi-Dchar M, Cassant-Sourdy S, Duluc C, et al. Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16. Gastroenterology 2015;148:1452–1465.
14. Zhang Y, Yan W, Collins MA, et al. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res 2013;73:6359–6374. 15. Funahashi H, Satake M, Dawson D, et al. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res 2007;67: 7068–7071. 16. Bousquet C, Guillermet-Guibert J, Saint-Laurent N, et al. Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. EMBO J 2006;25:3943–3954. 17. Deng L, Chen N, Li Y, et al. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim Biophys Acta 2010;1806:42–49. 18. Liou GY, Doppler H, Necela B, et al. Macrophagesecreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. J Cell Biol 2013;202:563–577. 19. McAllister F, Bailey JM, Alsina J, et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 2014;25:621–637. 20. Navas C, Hernandez-Porras I, Schuhmacher AJ, et al. EGF receptor signaling is essential for k-ras oncogenedriven pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:318–330. Reprint requests Address requests for reprints to: Howard C. Crawford, Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, NCRC Bldg 520, Room 1347, 1600 Huron Parkway Ann Arbor, Michigan. 48109-1600. e-mail: [email protected].
Conflicts of interest The author discloses no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.025
1281
