Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

Abstract

In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8-14-fold) as compared to sensitive tumors, and was increased (2-4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN failed to demonstrate implication in resistance to CPT-11 in vitro but could influence sensitivity to CPT-11 exclusively through an in vivo mechanism. Indeed, vasculature was significantly enhanced in resistant NB xenografts compared to sensitive and reverted xenografts, and we suggest that PTN is acting in our resistant in vivo NB model as an angiostatic factor.

Subclassification and Individual Survival Time Prediction from Gene Expression Data of Neuroblastoma Patients by Using CASPAR

“…32 Regarding the latter category, two interacting partners, ALK (anaplastic lymphoma kinase) and one of its ligands, the secreted growth factor PTN (pleiptrophin), were both selected to indicate outcome of neuroblastoma patients. PTN was negatively correlated with poor survival (i.e., higher expression values correlate with better outcome), which is in line with reports by Calvet et al (53), who showed that PTN expression was downregulated in neuroblastoma resistant to certain cytostatic drugs and also with a study by Nakagawara and colleagues, who showed that PTN expression is correlated with lower tumor stages and a better prognosis (54). ALK, one of the receptors of the PTN protein, has a specific role in the development of the embryonic nervous system (55) and was found to be positively correlated with poor outcome (i.e., higher expression values correlate with poor outcome).…”

The role of pleiotrophin in bone repair

“…Antisense PTN expression in human prostate LNCaP cells decreases prostate cancer cell-induced angiogenesis in vitro and in vivo [71,72]. On the other hand, antisense PTN expression in rat glioma C6 cells decreases glioma cell-induced angiogenesis in vitro and in vivo [73] and PTN seems to act as an angiostatic factor in an in vivo neuroblastoma model that is resistant to irinotecan [74]. In both cases, its regulatory effect on VEGF actions has been discussed as the most likely mechanism.…”

Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up‐regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase β/ζ

“…1,10,11,30,31 Although the reasons for these discrepancies remain unclear, it is interesting to note that at least in some cases, the existing data suggest common effects of both molecules. For example, PTN acts as an angiostatic factor in an in vivo neuroblastoma model resistant to the DNA-topoisomerase I inhibitor irinotecan, 32 and NO has been also reported as an antiangiogenic molecule in neuroblastomas. 33 The mRNA levels of both PTN and RPTPb/f are decreased in colorectal cancers as compared with those in adjacent normal mucosa 34 and eNOS expression in colorectal carcinoma is significantly lower than in non-neoplasm colorectal mucosa, 35 while NO induces apoptosis in colon cancer cells 36,37 via ERK[1/2] activation.…”