Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of ...pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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•IL-17+ T cells are recruited to the pancreas in response to Kras and inflammation•IL-17A overexpression accelerates PanIN initiation and progression•Inhibition of IL-17 signaling effectively prevents PanIN initiation and progression•Kras activates expression of functional IL-17 receptors on PanIN epithelium
McAllister et al. show that KrasG12D induces IL-17 receptors expression on PanIN epithelial cells and stimulates infiltration of IL-17-producing immune cells in a murine PanIN model, the latter of which is confirmed in human PanIN and that inhibition of IL-17 signaling prevents pancreatic neoplasia initiation.
Enzalutamide and abiraterone target the androgen receptor and androgen synthesis and are used to treat castration-resistant prostate cancer. A splice variant of the androgen receptor is associated ...with resistance to both drugs.
It is now accepted that castration-resistant prostate cancer is not androgen-independent and continues to rely on androgen signaling.
1
Owing to this new understanding, several drugs have recently emerged for the treatment of castration-resistant prostate cancer; these agents either suppress the synthesis of extragonadal androgens or target the androgen receptor directly.
2
Enzalutamide is an inhibitor of androgen-receptor signaling that exerts its activity by binding avidly to the ligand-binding domain of the androgen receptor, competing with and displacing the natural ligands of this receptor (testosterone and dihydrotestosterone) while also inhibiting translocation of the androgen receptor into the nucleus and impairing transcriptional activation . . .
The intracellular protein p120 catenin aids in maintenance of cell–cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in ...pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120f/f pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development.
•We examine the consequences of deletion of p120 catenin in mouse pancreas development.•p120 is required for proper pancreatic tubulogenesis and branching morphogenesis.•p120 deletion results in induction of inflammation in developing and adult pancreas.•Despite p120 loss, E-cadherin, β-catenin, and α-catenin are retained in development.•Family members ARVCF, δ-catenin, and p0071 might partially compensate for p120 loss.
Abstract The O2 sensitivity of the neonatal rat carotid body is increased after 1 day in moderate hyperoxia (60% O2 ) ( Donnelly et al., 2009 ). We investigated whether this enhanced peripheral ...chemosensitivity increases the hypoxic ventilatory response (HVR) and tested the hypothesis that this plasticity is mediated by the superoxide anion. Neonatal rats (7 d old) were injected with saline or MnTMPyP, a superoxide scavenger, and placed into 60% O2 for 23–28 h. Baseline ventilation was reduced and the acute HVR (12% O2 ) was enhanced in hyperoxia-treated rats relative to age-matched controls; MnTMPyP did not block these effects. An additional group of rats was studied after only 30 min in 60% O2 . This shorter exposure had no effect on normoxic ventilation or the HVR. We conclude that 1 d, but not 30 min, of 60% O2 augments the HVR of neonatal rats and that production of the superoxide anion does not contribute to this plasticity.
The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in ...endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine-based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis.
The O2 sensitivity of single‐unit carotid body chemoreceptor cells is increased in neonatal rats after a one‐day exposure to moderate hyperoxia (60% O2) (Donnelly et al., Respir. Physiol. Neurobiol. ...168: 189–197, 2009). To determine whether the hypoxic ventilatory response (HVR) is similarly enhanced by this exposure, we measured the acute HVR of neonatal rats (P8) by head‐body plethysmography immediately after 23–28 h in 60% O2. The HVR was increased by ~50% in hyperoxia‐treated rats due to a larger increase in tidal volume. This effect was not blocked by administration of the antioxidant drug MnTMPyP, suggesting that this plasticity is not mediated by increased production of the superoxide anion. Moreover, a shorter exposure to 60% O2 (30 min) did not alter the HVR. In contrast to prolonged hyperoxic exposures that diminish the HVR, we conclude that short periods of hyperoxia (~ 1 d) augment the HVR of neonatal rats. The mechanisms underlying this plasticity will require further investigation. Supported by NIH grant HL‐083972.
Abstract
Background: Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor (AR) protein which lacks the ligand-binding domain, the target of enzalutamide, but ...remains constitutively active as a transcription factor. Following from preclinical studies implicating AR-V7 as a mechanism of resistance to novel AR-directed therapies, we hypothesized that the presence of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with primary resistance to enzalutamide.
Methods: We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) analysis to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with enzalutamide. We examined associations between AR-V7 status and PSA response rates (the primary clinical endpoint of the study), PSA-progression-free-survival (PSA-PFS), and clinical/radiographic-progression-free-survival (PFS). Multivariable Cox regressions were performed to determine the independent effect of AR-V7 status on clinical outcomes to enzalutamide treatment. A prespecified sample size of 30 patients would yield 85% power to detect a difference in PSA response rates from 10% (in AR-V7-positive men) to 60% (in AR-V7-negative men), using a two-sided α=0.10.
Results: Thirty-one (31) enzalutamide-treated patients were enrolled in the study, of which 38.7% (12/31) had detectable AR-V7 mRNA from CTCs. Compared to AR-V7-negative patients, AR-V7-positive men had worse PSA response rates (0% 0/12 vs 52.6% 10/19, P=0.004); in fact, no patient with detectable AR-V7 achieved a PSA response. Furthermore, AR-V7-positive patients had shorter PSA-PFS (median: 1.4 vs 5.9 months, HR 7.4, 95%CI 2.7-20.6, log-rank P<0.001), and shorter PFS (median: 2.1 vs 6.1 months, HR 8.5, 95%CI 2.8-25.4, log-rank P<0.001) than AR-V7-negative patients. In multivariable Cox regression analysis, presence of AR-V7 (HR 3.5, 95%CI 1.2-10.5, P=0.027), baseline PSA level (HR 1.01, 95%CI 1.00-1.01, P=0.042), and prior abiraterone treatment (HR 5.4, 95%CI 1.1-26.5, P=0.039) were all independently predictive of PSA-PFS. Similarly, presence of AR-V7 (HR 3.7, 95%CI 1.2-11.9, P=0.026) and prior abiraterone use (HR 8.7, 95%CI 1.0-75.6, P=0.049) were both independently predictive of PFS in multivariable analysis.
Conclusions: Detection of AR-V7 mRNA in circulating tumor cells from patients with metastatic castration-resistant prostate cancer may be associated with primary resistance to enzalutamide. If confirmed by other investigators in larger-scale prospective studies, this could be used as a biomarker to predict enzalutamide resistance (and to direct AR-V7-positive patients away from further AR-targeting therapies).
Citation Format: Emmanuel S. Antonarakis, Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen, Helen L. Fedor, Tamara L. Lotan, Angelo M. De Marzo, John T. Isaacs, William B. Isaacs, Rosa Nadal, Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, Mario A. Eisenberger, Jun Luo. Androgen receptor splice variant-7 predicts resistance to enzalutamide in patients with castration-resistant prostate cancer. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2014-2910
The O
2
sensitivity of the neonatal rat carotid body is increased after one day in moderate hyperoxia (60% O
2
) (Donnelly et al., Respir. Physiol. Neurobiol. 168: 189–197, 2009). We investigated ...whether this enhanced peripheral chemosensitivity increases the hypoxic ventilatory response (HVR) and tested the hypothesis that this plasticity is mediated by the superoxide anion. Neonatal rats (7 d old) were injected with saline or MnTMPyP, a superoxide scavenger, and placed into 60% O
2
for 23–28 h. Baseline ventilation was reduced and the acute HVR (12% O
2
) was enhanced in hyperoxia-treated rats relative to age-matched controls; MnTMPyP did not block these effects. An additional group of rats was studied after only 30 min in 60% O
2
. This shorter exposure had no effect on normoxic ventilation or the HVR. We conclude that 1 d, but not 30 min, of 60% O
2
augments the HVR of neonatal rats and that production of the superoxide anion does not contribute to this plasticity.
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