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Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals.

Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, Chang L, Song W, Chang HC, Krolewski JJ, Nastiuk KL, Yeh S, Chang C - Oncotarget (2015)

Bottom Line: Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals.The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling.Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.

ABSTRACT
High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-β1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

No MeSH data available.


Related in: MedlinePlus

Pre-adipocytes promote PCa invasion using in vivo orthotopic PCa modelA. Orthotopic-implantation of human immortalized pre-adipocytes together with PCa promotes PCa invasion cells. The CWR22Rv1 (22Rv1) cells were transfected with pCDNA-luciferase. 22Rv1-luc cells (1 × 106) were mixed with or without pre-adipocytes (1 × 105) and orthotopically implanted into the AP of nude mice. After 6 weeks implantation, the PCa growth was monitored by IVIS images. Arrows show the metastatic foci. B. Quantification data for tumor metastases in mice. C. Image illustrates metastasized tumors in the diaphragm. The top panels show the tumor mass on diaphragm, and the bottom panels are the H&E staining to confirm the tumor mass is cancer. Arrows show the metastatic foci. D. IHC staining for AR, TGF-β1 and MMP-9 in orthotopic mice tumor tissues.
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Figure 5: Pre-adipocytes promote PCa invasion using in vivo orthotopic PCa modelA. Orthotopic-implantation of human immortalized pre-adipocytes together with PCa promotes PCa invasion cells. The CWR22Rv1 (22Rv1) cells were transfected with pCDNA-luciferase. 22Rv1-luc cells (1 × 106) were mixed with or without pre-adipocytes (1 × 105) and orthotopically implanted into the AP of nude mice. After 6 weeks implantation, the PCa growth was monitored by IVIS images. Arrows show the metastatic foci. B. Quantification data for tumor metastases in mice. C. Image illustrates metastasized tumors in the diaphragm. The top panels show the tumor mass on diaphragm, and the bottom panels are the H&E staining to confirm the tumor mass is cancer. Arrows show the metastatic foci. D. IHC staining for AR, TGF-β1 and MMP-9 in orthotopic mice tumor tissues.

Mentions: To demonstrate all above in vitro cell lines results in the in vivo animal models, we then orthotopically xenografted PCa cells into the anterior prostates (AP) of mice using CWR22Rv1 cells stably transfected with pCDNA-luciferase to monitor the PCa progression with IVIS Imaging system [8]. After xenografting 1 × 106 PCa CWR22Rv1-luc cells with or without mixed 1 × 105 human immortalized pre-adipocytes for six weeks, we found (from IVIS image) metastatic foci, marked by arrows (Fig. 5A), in 4 out of 5 mice with co-implanted PCa and pre-adipocyte cells. In contrast, no metastatic foci were found in mice with PCa CWR22Rv1-luc cells (Fig. 5A-B). These results from IVIS image were further confirmed showing identified metastatic foci in the diaphragm and H&E staining after mice were sacrificed (Fig. 5C).


Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals.

Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, Chang L, Song W, Chang HC, Krolewski JJ, Nastiuk KL, Yeh S, Chang C - Oncotarget (2015)

Pre-adipocytes promote PCa invasion using in vivo orthotopic PCa modelA. Orthotopic-implantation of human immortalized pre-adipocytes together with PCa promotes PCa invasion cells. The CWR22Rv1 (22Rv1) cells were transfected with pCDNA-luciferase. 22Rv1-luc cells (1 × 106) were mixed with or without pre-adipocytes (1 × 105) and orthotopically implanted into the AP of nude mice. After 6 weeks implantation, the PCa growth was monitored by IVIS images. Arrows show the metastatic foci. B. Quantification data for tumor metastases in mice. C. Image illustrates metastasized tumors in the diaphragm. The top panels show the tumor mass on diaphragm, and the bottom panels are the H&E staining to confirm the tumor mass is cancer. Arrows show the metastatic foci. D. IHC staining for AR, TGF-β1 and MMP-9 in orthotopic mice tumor tissues.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494941&req=5

Figure 5: Pre-adipocytes promote PCa invasion using in vivo orthotopic PCa modelA. Orthotopic-implantation of human immortalized pre-adipocytes together with PCa promotes PCa invasion cells. The CWR22Rv1 (22Rv1) cells were transfected with pCDNA-luciferase. 22Rv1-luc cells (1 × 106) were mixed with or without pre-adipocytes (1 × 105) and orthotopically implanted into the AP of nude mice. After 6 weeks implantation, the PCa growth was monitored by IVIS images. Arrows show the metastatic foci. B. Quantification data for tumor metastases in mice. C. Image illustrates metastasized tumors in the diaphragm. The top panels show the tumor mass on diaphragm, and the bottom panels are the H&E staining to confirm the tumor mass is cancer. Arrows show the metastatic foci. D. IHC staining for AR, TGF-β1 and MMP-9 in orthotopic mice tumor tissues.
Mentions: To demonstrate all above in vitro cell lines results in the in vivo animal models, we then orthotopically xenografted PCa cells into the anterior prostates (AP) of mice using CWR22Rv1 cells stably transfected with pCDNA-luciferase to monitor the PCa progression with IVIS Imaging system [8]. After xenografting 1 × 106 PCa CWR22Rv1-luc cells with or without mixed 1 × 105 human immortalized pre-adipocytes for six weeks, we found (from IVIS image) metastatic foci, marked by arrows (Fig. 5A), in 4 out of 5 mice with co-implanted PCa and pre-adipocyte cells. In contrast, no metastatic foci were found in mice with PCa CWR22Rv1-luc cells (Fig. 5A-B). These results from IVIS image were further confirmed showing identified metastatic foci in the diaphragm and H&E staining after mice were sacrificed (Fig. 5C).

Bottom Line: Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals.The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling.Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.

ABSTRACT
High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-β1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

No MeSH data available.


Related in: MedlinePlus