Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer

Abstract

The role of Notch signaling in prostate cancer has not been defined definitively. Several large scale tissue microarray studies revealed that the expression of some Notch signaling components including the Jagged1 ligand are upregulated in advanced human prostate cancer specimens. Jagged1 expressed by tumor cells may activate Notch signaling in both adjacent tumor cells and cells in tumor microenvironment. However, it remains undetermined whether increased Jagged1 expression reflects a cause for or a consequence of tumor progression in vivo. To address this question, we generated a novel R26-LSL-JAG1 mouse model that enables spatiotemporal Jagged1 expression. Prostate specific upregulation of Jagged1 neither interferes with prostate epithelial homeostasis nor significantly accelerates tumor initiation or progression in the prostate-specific Pten deletion mouse model for prostate cancer. However, Jagged1 upregulation results in increased inflammatory foci in tumors and incidence of intracystic adenocarcinoma. In addition, Jagged1 overexpression upregulates Tgfβ signaling in prostate stromal cells and promotes progression of a reactive stromal microenvironment in the Pten null prostate cancer model. Collectively, Jagged1 overexpression does not significantly accelerate prostate cancer initiation and progression in the context of loss-of-function of Pten, but alters tumor histopathology and microenvironment. Our study also highlights an understudied role of Notch signaling in regulating prostatic stromal homeostasis.

Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate

“…It should be noted that Pten L/L :PB-Cre4 mice in this study developed prostate tumors relatively more slowly than those in the previous report (30). Actually, our above observation on Pten L/L :PB-Cre4 mice was in agreement with a few other studies (26,64), although the precise reasons for the difference is not clear.…”

“…We observed that Pten L/L :PB-Cre4 mice develop intracystic carcinomas between 4 and 10 months of age and adenocarcinoma and invasive carcinomas after 10 months ( Table 1). The representative images show corresponding pathologic changes, with features typical of prostatic adenocarcinomas and invasive car-cinomas as reported previously (26) (Fig. 2, E1-E3).…”

Notch Signaling in the Tumor Microenvironment

“…It is likely that these intrinsic mechanisms are modified in a tumoral context where the aberrant vessels are in contact with other tumor compartments expressing ligands that may influence the vascular architecture. In particular, Jag1 expressed by tumor cells has an important impact on promoting tumor vascularization (Lin et al, 2017;Su et al, 2017;Zeng et al, 2005) (Table 1). Indeed, in a seminal study, co-injection of ECs with cancer cells overexpressing Jag1 led to an increase in micro-vessel density and increased tumor growth (Zeng et al, 2005).…”

“…This may be due, at least in part, to the inhibition by tumorderived Jag1 of Notch3-dependent cell death in ECs (Lin et al, 2017). In prostate cancer, Jag1 overexpression by cancer cells has also been shown to increase vascularization and inflammatory foci (Su et al, 2017). Tumor-induced Notch activation in the endothelium can also lead to EC senescence through Notch1 activation in ECs by tumor and myeloid cells, which induces inflammation and increases metastasis (Wieland et al, 2017).…”

“…The effect of Notch signaling in the reactive stroma may also depend on the stage of tumor progression. Indeed, in a prostate cancer model, Jag1 expression by cancer cells has been shown to promote an increase in activated fibroblasts expressing a-SMA and development of a reactive stroma with increased tenascin-C and collagen (Su et al, 2017). In this case, activation of Notch rather than its loss is implicated in the activation of fibroblasts.…”