Inducible re-expression of p16 in an orthotopic mouse model of pancreatic cancer inhibits lymphangiogenesis and lymphatic metastasis

Schulz, Petra; Scholz, Arne; Rexin, A.; Hauff, Peter; Schirner, Michael; Wiedenmann, Bertram; Detjen, Katharina

doi:10.1038/sj.bjc.6604457

Cited by 26 publications

(30 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…45,46 Some authors have suggested that p16 INK4a plays a major role not only in suppression of cell division but also in suppression of lymphangiogenesis and lymphatic metastasis. 45 As far as we are concerned, the role of p16 INK4a immunoexpression as a marker for survival in PSCC has only been evaluated in 1 previous study and an association with a better overall survival was detected.…”

Section: Discussionmentioning

confidence: 99%

Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: Correlation with pathologic subtypes, p16INK4a expression, and prognosis

Ferrándiz-Pulido

Masferrer

Torres

et al. 2013

Journal of the American Academy of Dermatology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: Correlation with pathologic subtypes, p16INK4a expression, and prognosis

Ferrándiz-Pulido

Masferrer

Torres

et al. 2013

Journal of the American Academy of Dermatology

View full text Add to dashboard Cite

“…Following sequential transfection of pcDNA6/TR (cells described in ref. 30) and pcDNA4/TO-SP3xflag-SLIT2-mycHis, SLIT2 expression was induced by 1 mg/mL doxycycline (Sigma-Aldrich). Cells expressing pcDNA6/TR were used to exclude off-target effects of doxycycline.…”

Section: Generation Of Cell Clonesmentioning

confidence: 99%

Axon Guidance Factor SLIT2 Inhibits Neural Invasion and Metastasis in Pancreatic Cancer

et al. 2014

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) metastasizes by neural, vascular, and local invasion routes, which limit patient survival. In nerves and vessels, SLIT2 and its ROBO receptors constitute repellent guidance cues that also direct epithelial branching. Thus, the SLIT2-ROBO system may represent a key pinch point to regulate PDAC spread. In this study, we examined the hypothesis that escaping from repellent SLIT2-ROBO signaling is essential to enable PDAC cells to appropriate their local stromal infrastructure for dissemination. Through immunohistochemical analysis, we detected SLIT2 receptors ROBO1 and ROBO4 on epithelia, nerves, and vessels in healthy pancreas and PDAC specimens, respectively. SLIT2 mRNA expression was reduced in PDAC compared with nontransformed pancreatic tissues and cell lines, suggesting a reduction in SLIT2-ROBO pathway activity in PDAC. In support of this interpretation, restoring the SLIT2 expression in SLIT2-deficient PDAC cells inhibited their bidirectional chemoattraction with neural cells, and more specifically, impaired unidirectional PDAC cell navigation along outgrowing neurites in models of neural invasion. Restoring autocrine/paracrine SLIT2 signaling was also sufficient to inhibit the directed motility of PDAC cells, but not their random movement. Conversely, RNA interference-mediated silencing of ROBO1 stimulated the motility of SLIT2-competent PDAC cells. Furthermore, culture supernatants from SLIT2-competent PDAC cells impaired migration of endothelial cells (human umbilical vein endothelial cells), whereas an N-terminal SLIT2 cleavage fragment stimulated such migration. In vivo investigations of pancreatic tumors with restored SLIT2 expression demonstrated reduced invasion, metastasis, and vascularization, with opposing effects produced by ROBO1 silencing in tumor cells or sequestration of endogenous SLIT2. Analysis of clinical specimens of PDAC showed that those with low SLIT2 mRNA expression exhibited a higher incidence and a higher fraction of tumor-infiltrated lymph nodes. Taken together, our findings argue that disrupting SLIT2-ROBO signaling in PDAC may enhance metastasis and predispose PDAC cells to neural invasion. Cancer Res; 74(5); 1529-40. Ó2014 AACR.

show abstract

“…In accordance to squamous cell carcinomas of other origins, we were able to demonstrate a more aggressive behavior of p16-negative tumors. Besides its impact in suppression of cell division, p16 seems to play a major role in suppression of lymphangiogenesis and lymphatic metastasis, since in vivo re-expression of p16 inhibited the process of lymphangiogenesis in pancreatic cancer [35].…”

Section: Discussionmentioning

confidence: 99%

Alterations in the tumor suppressor gene p16 INK4A are associated with aggressive behavior of penile carcinomas

Poetsch¹,

Hemmerich²,

Kakies

et al. 2010

Virchows Arch

View full text Add to dashboard Cite

Alterations in the p16/cyclinD1/Rb and ARF/Mdm2/p53 pathways are frequent events in the pathogenesis of squamous cell carcinomas. Different mechanisms of p16 regulation have been described for penile carcinomas so far. Therefore, expression of p16 and p53 was immunohistochemically detected with monoclonal antibodies in 52 primary invasive penile squamous cell carcinomas. The carcinomas were analyzed for allelic loss (LOH) in p16(INK4A) and p53, as well as for mutations in the p16(INK4A) and the p53 gene. In addition, we examined the promoter status of p16(INK4A) by methylation-specific PCR. The presence of human papilloma virus (HPV) 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Data were compared to clinical data. Concerning p16, 26 (50%) tumors showed positive immunohistochemistry, 32 (62%) tumors showed allelic loss and 22 tumors (42%) showed promoter hypermethylation. All tumors with negative p16 immunohistochemistry showed LOH near the p16(INK4A) locus and/or hypermethylation of the p16(INK4A) promoter. HPV 16 DNA was detected in 17 tumors, ten of them with positive p16 immunostaining. The remaining seven tumors with negative p16 staining showed allelic loss and/or promoter hypermethylation. Evidence of lymph node metastasis was significantly associated with negative p16 immunohistochemistry as well as with combined LOH and promoter hypermethylation (p = 0.003 and p = 0.018, respectively). Allelic loss around p53 was found in 22 tumors (42%), and seven mutations of the p53 gene could be demonstrated in our tumors. No correlations could be found between any p53 alteration and clinical parameters.

show abstract

Inducible re-expression of p16 in an orthotopic mouse model of pancreatic cancer inhibits lymphangiogenesis and lymphatic metastasis

Cited by 26 publications

References 33 publications

Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: Correlation with pathologic subtypes, p16INK4a expression, and prognosis

Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: Correlation with pathologic subtypes, p16INK4a expression, and prognosis

Axon Guidance Factor SLIT2 Inhibits Neural Invasion and Metastasis in Pancreatic Cancer

Alterations in the tumor suppressor gene p16 INK4A are associated with aggressive behavior of penile carcinomas

Contact Info

Product

Resources

About