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A switch from CD44⁺ cell to EMT cell drives the metastasis of prostate cancer.

Shang Z, Cai Q, Zhang M, Zhu S, Ma Y, Sun L, Jiang N, Tian J, Niu X, Chen J, Sun Y, Niu Y - Oncotarget (2015)

Bottom Line: Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT.Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion.Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

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Related in: MedlinePlus

TGFβ1 can activate the dedifferentiation of PCa cells, leading to increased CD44+ S/P cell population(a) TGFβ1 was detected by IHC in human PCa samples before ADT, after ADT for 3 month, and of CRPC specimens. TGFβ1 expression was increased after ADT therapy. (b) TGFβ1 and phospho-Smad2/3 expression were increased in 16wks and 24wks castrated TRAMP prostate tumors comparing to wt TRAMP tumors. (c) TGFβ1 could expanse CD44+ cell population in vitro. LNCaP cells and CWR22rv1 cells were treated by 5ng/ml TGFβ1 for 3, 6, 9, and 12hrs. The CD44+ cell population was separated by flow cytometry. (d) 5ng/ml TGFβ1 increased the expression of cancer stem-like cell markers, including CD44, Oct-4, c-met, nanog and sox2 in LNCaP cells by real-time PCR assay. Data are in triplicate from three independent experiments and were normalized to GAPDH. All data are expressed as mean±S.D. (e) 5ng/ml TGFβ1 could also induce more sphere formation the character of S/P cells, compared to non-treatment LNCaP cells. Quantitation of the numbers of spheres (diameter>40μm) are presented as the mean SD (Scale bar, 100μm). (f) 5ng/ml TGFβ1 could up-regulate the expression of CD44 in LNCaP and CWR22RV1 cells via Western blot assay.(g) Importantly, We also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased in Western blot assay. Significance was defined as p<0.05(*).
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Figure 3: TGFβ1 can activate the dedifferentiation of PCa cells, leading to increased CD44+ S/P cell population(a) TGFβ1 was detected by IHC in human PCa samples before ADT, after ADT for 3 month, and of CRPC specimens. TGFβ1 expression was increased after ADT therapy. (b) TGFβ1 and phospho-Smad2/3 expression were increased in 16wks and 24wks castrated TRAMP prostate tumors comparing to wt TRAMP tumors. (c) TGFβ1 could expanse CD44+ cell population in vitro. LNCaP cells and CWR22rv1 cells were treated by 5ng/ml TGFβ1 for 3, 6, 9, and 12hrs. The CD44+ cell population was separated by flow cytometry. (d) 5ng/ml TGFβ1 increased the expression of cancer stem-like cell markers, including CD44, Oct-4, c-met, nanog and sox2 in LNCaP cells by real-time PCR assay. Data are in triplicate from three independent experiments and were normalized to GAPDH. All data are expressed as mean±S.D. (e) 5ng/ml TGFβ1 could also induce more sphere formation the character of S/P cells, compared to non-treatment LNCaP cells. Quantitation of the numbers of spheres (diameter>40μm) are presented as the mean SD (Scale bar, 100μm). (f) 5ng/ml TGFβ1 could up-regulate the expression of CD44 in LNCaP and CWR22RV1 cells via Western blot assay.(g) Importantly, We also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased in Western blot assay. Significance was defined as p<0.05(*).

Mentions: Previously studies found that activated AR might suppress TGFβ1 expression at transcriptional regulation, and ADT might lead to increased expression of TGFβ1 and TGFβ1 receptors plus its downstream Smad3. Here we found TGFβ1 signaling could also go through modulation EMT signaling and alternation the cancer stem-like cell population. As shown in Fig. 3c, TGFβ1 could enhance CD44+ cell population (via flow cytometry assay) in LNCaP and CWR22RV1 cells. Furthermore, TGFβ1 also increased cancer stem-like cell markers expression in LNCaP cells including CD44, Oct-4, c-met, nanog, sox2, and induced more sphere formation (that represent cancer stem-like cell formation) compared to wide type LNCaP cells (Fig. 3d&3e). Interestingly, TGFβ1 could also up-regulate cancer stem-like cell marker CD44 expression (via Western blot assay). Importantly, we also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased by Western blot (Fig. 3f&3g).


A switch from CD44⁺ cell to EMT cell drives the metastasis of prostate cancer.

Shang Z, Cai Q, Zhang M, Zhu S, Ma Y, Sun L, Jiang N, Tian J, Niu X, Chen J, Sun Y, Niu Y - Oncotarget (2015)

TGFβ1 can activate the dedifferentiation of PCa cells, leading to increased CD44+ S/P cell population(a) TGFβ1 was detected by IHC in human PCa samples before ADT, after ADT for 3 month, and of CRPC specimens. TGFβ1 expression was increased after ADT therapy. (b) TGFβ1 and phospho-Smad2/3 expression were increased in 16wks and 24wks castrated TRAMP prostate tumors comparing to wt TRAMP tumors. (c) TGFβ1 could expanse CD44+ cell population in vitro. LNCaP cells and CWR22rv1 cells were treated by 5ng/ml TGFβ1 for 3, 6, 9, and 12hrs. The CD44+ cell population was separated by flow cytometry. (d) 5ng/ml TGFβ1 increased the expression of cancer stem-like cell markers, including CD44, Oct-4, c-met, nanog and sox2 in LNCaP cells by real-time PCR assay. Data are in triplicate from three independent experiments and were normalized to GAPDH. All data are expressed as mean±S.D. (e) 5ng/ml TGFβ1 could also induce more sphere formation the character of S/P cells, compared to non-treatment LNCaP cells. Quantitation of the numbers of spheres (diameter>40μm) are presented as the mean SD (Scale bar, 100μm). (f) 5ng/ml TGFβ1 could up-regulate the expression of CD44 in LNCaP and CWR22RV1 cells via Western blot assay.(g) Importantly, We also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased in Western blot assay. Significance was defined as p<0.05(*).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359227&req=5

Figure 3: TGFβ1 can activate the dedifferentiation of PCa cells, leading to increased CD44+ S/P cell population(a) TGFβ1 was detected by IHC in human PCa samples before ADT, after ADT for 3 month, and of CRPC specimens. TGFβ1 expression was increased after ADT therapy. (b) TGFβ1 and phospho-Smad2/3 expression were increased in 16wks and 24wks castrated TRAMP prostate tumors comparing to wt TRAMP tumors. (c) TGFβ1 could expanse CD44+ cell population in vitro. LNCaP cells and CWR22rv1 cells were treated by 5ng/ml TGFβ1 for 3, 6, 9, and 12hrs. The CD44+ cell population was separated by flow cytometry. (d) 5ng/ml TGFβ1 increased the expression of cancer stem-like cell markers, including CD44, Oct-4, c-met, nanog and sox2 in LNCaP cells by real-time PCR assay. Data are in triplicate from three independent experiments and were normalized to GAPDH. All data are expressed as mean±S.D. (e) 5ng/ml TGFβ1 could also induce more sphere formation the character of S/P cells, compared to non-treatment LNCaP cells. Quantitation of the numbers of spheres (diameter>40μm) are presented as the mean SD (Scale bar, 100μm). (f) 5ng/ml TGFβ1 could up-regulate the expression of CD44 in LNCaP and CWR22RV1 cells via Western blot assay.(g) Importantly, We also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased in Western blot assay. Significance was defined as p<0.05(*).
Mentions: Previously studies found that activated AR might suppress TGFβ1 expression at transcriptional regulation, and ADT might lead to increased expression of TGFβ1 and TGFβ1 receptors plus its downstream Smad3. Here we found TGFβ1 signaling could also go through modulation EMT signaling and alternation the cancer stem-like cell population. As shown in Fig. 3c, TGFβ1 could enhance CD44+ cell population (via flow cytometry assay) in LNCaP and CWR22RV1 cells. Furthermore, TGFβ1 also increased cancer stem-like cell markers expression in LNCaP cells including CD44, Oct-4, c-met, nanog, sox2, and induced more sphere formation (that represent cancer stem-like cell formation) compared to wide type LNCaP cells (Fig. 3d&3e). Interestingly, TGFβ1 could also up-regulate cancer stem-like cell marker CD44 expression (via Western blot assay). Importantly, we also applied interruption approach via using SB431542 to block TGFβ1 signaling and found CD44 expression decreased by Western blot (Fig. 3f&3g).

Bottom Line: Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT.Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion.Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

Show MeSH
Related in: MedlinePlus