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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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Targeting CD44 led to decrease PCa EMT and metastasis in vivo(a) Salinomycin can significantly suppress CD44 expression. CD44 expression was detected in LNCaP and CWR22RV1 cell lines treated with salinomycin by Western blot. (b) 5×106CWR22rv1 were subcutaneously implanted on the dorsal of nude mice with androgen recruitment. After tumor diameter reached to 0.8cm, the tumor was harvested, divided into equal pieces and orthotopically transplanted into anterior prostates of either castrated or non-castrated nude mice. Each 5 from 10 castrated and 10 non castrated nude mice was treated with salinomycin by intraperitoneal injection, the others were intraperitoneally treated with corn oil as control. Metastatic tumors were found in salinomycin treatment groups as compared to those found from control groups. (c) The expressions of CD44, E-Cadherin, Vimentin, SOX2, c-Met and Oct-4 were analyzed by IHC. Quantitation was analyzed by image pro-plus 6.0 software. Significance was defined as p<0.05(*).
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Figure 6: Targeting CD44 led to decrease PCa EMT and metastasis in vivo(a) Salinomycin can significantly suppress CD44 expression. CD44 expression was detected in LNCaP and CWR22RV1 cell lines treated with salinomycin by Western blot. (b) 5×106CWR22rv1 were subcutaneously implanted on the dorsal of nude mice with androgen recruitment. After tumor diameter reached to 0.8cm, the tumor was harvested, divided into equal pieces and orthotopically transplanted into anterior prostates of either castrated or non-castrated nude mice. Each 5 from 10 castrated and 10 non castrated nude mice was treated with salinomycin by intraperitoneal injection, the others were intraperitoneally treated with corn oil as control. Metastatic tumors were found in salinomycin treatment groups as compared to those found from control groups. (c) The expressions of CD44, E-Cadherin, Vimentin, SOX2, c-Met and Oct-4 were analyzed by IHC. Quantitation was analyzed by image pro-plus 6.0 software. Significance was defined as p<0.05(*).

Mentions: All above results suggest ADT to TGFβ1 to CD44 to EMT to PCa metastasis may represent a key signaling to influence the PCa metastasis. We are interested to see if target this newly identified signaling may yield any major impact on PCa metastasis. We then target CD44 with salinomycin to examine its therapeutic effect on the PCa progression. We first treated LNCaP and CWR22rv1 cell with salinomycin and found that salinomycin could decrease CD44 expression (Fig. 6a). We then applied CWR22rv1 xenograft mouse model via subcutaneously implanted 1×107 CWR22rv1 cell on the dorsal prostate of nude mice. After tumor diameter reached to 0.8cm, it was divided into equal pieces and transplanted into the both prostate anterior lobe of castrated nude mice. One group of the mice were treated with salinomycin by intra-peritoneal injection, the others was intra-peritoneal injection with corn oil as control. The results showed the mice treated with salinomycin developed less malignant metastatic tumor as compared to those found from control group (Fig. 6b). Importantly, we also found decreased CD44 expression, with altered EMT markers for the decreased vimentin and increased E-Cadherin in the tumor with salinomycin treatment compared to those from control group (Fig. 6c). Furthermore, the expression of cancer stem cell markers like c-Met, Sox2, Oct-4 were also decreased in the tumor with salinomycin treatment compared to those from control group (Fig.6c).


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)

Targeting CD44 led to decrease PCa EMT and metastasis in vivo(a) Salinomycin can significantly suppress CD44 expression. CD44 expression was detected in LNCaP and CWR22RV1 cell lines treated with salinomycin by Western blot. (b) 5×106CWR22rv1 were subcutaneously implanted on the dorsal of nude mice with androgen recruitment. After tumor diameter reached to 0.8cm, the tumor was harvested, divided into equal pieces and orthotopically transplanted into anterior prostates of either castrated or non-castrated nude mice. Each 5 from 10 castrated and 10 non castrated nude mice was treated with salinomycin by intraperitoneal injection, the others were intraperitoneally treated with corn oil as control. Metastatic tumors were found in salinomycin treatment groups as compared to those found from control groups. (c) The expressions of CD44, E-Cadherin, Vimentin, SOX2, c-Met and Oct-4 were analyzed by IHC. Quantitation was analyzed by image pro-plus 6.0 software. Significance was defined as p<0.05(*).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4359227&req=5

Figure 6: Targeting CD44 led to decrease PCa EMT and metastasis in vivo(a) Salinomycin can significantly suppress CD44 expression. CD44 expression was detected in LNCaP and CWR22RV1 cell lines treated with salinomycin by Western blot. (b) 5×106CWR22rv1 were subcutaneously implanted on the dorsal of nude mice with androgen recruitment. After tumor diameter reached to 0.8cm, the tumor was harvested, divided into equal pieces and orthotopically transplanted into anterior prostates of either castrated or non-castrated nude mice. Each 5 from 10 castrated and 10 non castrated nude mice was treated with salinomycin by intraperitoneal injection, the others were intraperitoneally treated with corn oil as control. Metastatic tumors were found in salinomycin treatment groups as compared to those found from control groups. (c) The expressions of CD44, E-Cadherin, Vimentin, SOX2, c-Met and Oct-4 were analyzed by IHC. Quantitation was analyzed by image pro-plus 6.0 software. Significance was defined as p<0.05(*).
Mentions: All above results suggest ADT to TGFβ1 to CD44 to EMT to PCa metastasis may represent a key signaling to influence the PCa metastasis. We are interested to see if target this newly identified signaling may yield any major impact on PCa metastasis. We then target CD44 with salinomycin to examine its therapeutic effect on the PCa progression. We first treated LNCaP and CWR22rv1 cell with salinomycin and found that salinomycin could decrease CD44 expression (Fig. 6a). We then applied CWR22rv1 xenograft mouse model via subcutaneously implanted 1×107 CWR22rv1 cell on the dorsal prostate of nude mice. After tumor diameter reached to 0.8cm, it was divided into equal pieces and transplanted into the both prostate anterior lobe of castrated nude mice. One group of the mice were treated with salinomycin by intra-peritoneal injection, the others was intra-peritoneal injection with corn oil as control. The results showed the mice treated with salinomycin developed less malignant metastatic tumor as compared to those found from control group (Fig. 6b). Importantly, we also found decreased CD44 expression, with altered EMT markers for the decreased vimentin and increased E-Cadherin in the tumor with salinomycin treatment compared to those from control group (Fig. 6c). Furthermore, the expression of cancer stem cell markers like c-Met, Sox2, Oct-4 were also decreased in the tumor with salinomycin treatment compared to those from control group (Fig.6c).

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