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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

ADT sequentially alters the cancer stem-like cell populations and promotes EMT in TRAMP PCa tumors(a) The protocol of TRAMP mice experiments was illustrated. TRAMP mice were castrated at 12-week-old. Tumor samples were collected and analyzed at 12wks, 16wks, 20wks, 24wks and 32wks. (b) The growth rates of prostate epithelium were demonstrated by BrdU incorporation in TRAMP prostate before and after castration. The mice were i.p. injected with BrdU (10 ug/g body weight) every 6hr, and killed 24hr later. Paraffin-fixed tissue sections were stained by the BrdU detecting kit (Zymed Laboratories). The castration decreased the BrdU incorporation rates in 16wks-old mouse prostates, while the BrdU incorporation rates began to increase from 20wks and even higher than pre-castration from about 24wks (P<0.05), indicating the happen of CRPC. (c) Considerable metastatic foci in lung kidney and liver of were gradually increased from 24-wk-castration TRAMP mice. (d) From 20wks to 24wks, the castration resistant tumor continually grew bigger in gross (the first and second upper row). H&E staining showed that castration resistant tumors are poorly differentiated from 16wks to 24wks tumor samples (the third row). When double staining CK5 (green, marker for basal epithelial cell) and CK8 (red, marker for luminal epithelial cell) in immunofluorescence examination, the decreasing CK8+ staining following castration were detected, and the increasing CK5+/CK8+(yellow color, overlapped by green and red signals) cells, which indicated the expansion of intermediate cell population, were noticed in 16wks and 20wks tumors (the fourth row). Interestingly, the staining for epithelial markers, both CK5 and CK8, was significantly diminished in 24wks tumors. The CD44 expression significantly increased in 20wks and 24wks of castration resistant tumors (the fifth row). And the expression of E-Cadherin significantly decreased in 20wks and 24wks of castration resistant tumors (the last row). Significance was defined as p<0.05(*). (e) To summarize the sequential events following castration. After the TRAMP mice were castrated in 12wks, the dedifferentiation of epithelium, characterized by expanded CK5+/CK8+ cell population, happened in 16wks, followed by the EMT transition on 20wks and metastasis on 24wks.
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Figure 2: ADT sequentially alters the cancer stem-like cell populations and promotes EMT in TRAMP PCa tumors(a) The protocol of TRAMP mice experiments was illustrated. TRAMP mice were castrated at 12-week-old. Tumor samples were collected and analyzed at 12wks, 16wks, 20wks, 24wks and 32wks. (b) The growth rates of prostate epithelium were demonstrated by BrdU incorporation in TRAMP prostate before and after castration. The mice were i.p. injected with BrdU (10 ug/g body weight) every 6hr, and killed 24hr later. Paraffin-fixed tissue sections were stained by the BrdU detecting kit (Zymed Laboratories). The castration decreased the BrdU incorporation rates in 16wks-old mouse prostates, while the BrdU incorporation rates began to increase from 20wks and even higher than pre-castration from about 24wks (P<0.05), indicating the happen of CRPC. (c) Considerable metastatic foci in lung kidney and liver of were gradually increased from 24-wk-castration TRAMP mice. (d) From 20wks to 24wks, the castration resistant tumor continually grew bigger in gross (the first and second upper row). H&E staining showed that castration resistant tumors are poorly differentiated from 16wks to 24wks tumor samples (the third row). When double staining CK5 (green, marker for basal epithelial cell) and CK8 (red, marker for luminal epithelial cell) in immunofluorescence examination, the decreasing CK8+ staining following castration were detected, and the increasing CK5+/CK8+(yellow color, overlapped by green and red signals) cells, which indicated the expansion of intermediate cell population, were noticed in 16wks and 20wks tumors (the fourth row). Interestingly, the staining for epithelial markers, both CK5 and CK8, was significantly diminished in 24wks tumors. The CD44 expression significantly increased in 20wks and 24wks of castration resistant tumors (the fifth row). And the expression of E-Cadherin significantly decreased in 20wks and 24wks of castration resistant tumors (the last row). Significance was defined as p<0.05(*). (e) To summarize the sequential events following castration. After the TRAMP mice were castrated in 12wks, the dedifferentiation of epithelium, characterized by expanded CK5+/CK8+ cell population, happened in 16wks, followed by the EMT transition on 20wks and metastasis on 24wks.

Mentions: In our TRAMP mouse model, mice were castrated at 12-weeks-old and tumor samples were collected at 16wks, 20 wks, 24wks, 28wks (Fig. 2a). We found that the proliferation marker, BrdU (and therefore, the growth rate too) was gradually increased from 16 wks tumors treated with ADT-castration to 32 wks tumor treated with ADT-castration castration tumor (Fig. 2b). In contrast, we found enhanced metastasis with more and more metastatic foci in liver, lung and kidney emerged from 24 wks tumor treated with ADT with castration (Fig. 2c).


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)

ADT sequentially alters the cancer stem-like cell populations and promotes EMT in TRAMP PCa tumors(a) The protocol of TRAMP mice experiments was illustrated. TRAMP mice were castrated at 12-week-old. Tumor samples were collected and analyzed at 12wks, 16wks, 20wks, 24wks and 32wks. (b) The growth rates of prostate epithelium were demonstrated by BrdU incorporation in TRAMP prostate before and after castration. The mice were i.p. injected with BrdU (10 ug/g body weight) every 6hr, and killed 24hr later. Paraffin-fixed tissue sections were stained by the BrdU detecting kit (Zymed Laboratories). The castration decreased the BrdU incorporation rates in 16wks-old mouse prostates, while the BrdU incorporation rates began to increase from 20wks and even higher than pre-castration from about 24wks (P<0.05), indicating the happen of CRPC. (c) Considerable metastatic foci in lung kidney and liver of were gradually increased from 24-wk-castration TRAMP mice. (d) From 20wks to 24wks, the castration resistant tumor continually grew bigger in gross (the first and second upper row). H&E staining showed that castration resistant tumors are poorly differentiated from 16wks to 24wks tumor samples (the third row). When double staining CK5 (green, marker for basal epithelial cell) and CK8 (red, marker for luminal epithelial cell) in immunofluorescence examination, the decreasing CK8+ staining following castration were detected, and the increasing CK5+/CK8+(yellow color, overlapped by green and red signals) cells, which indicated the expansion of intermediate cell population, were noticed in 16wks and 20wks tumors (the fourth row). Interestingly, the staining for epithelial markers, both CK5 and CK8, was significantly diminished in 24wks tumors. The CD44 expression significantly increased in 20wks and 24wks of castration resistant tumors (the fifth row). And the expression of E-Cadherin significantly decreased in 20wks and 24wks of castration resistant tumors (the last row). Significance was defined as p<0.05(*). (e) To summarize the sequential events following castration. After the TRAMP mice were castrated in 12wks, the dedifferentiation of epithelium, characterized by expanded CK5+/CK8+ cell population, happened in 16wks, followed by the EMT transition on 20wks and metastasis on 24wks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: ADT sequentially alters the cancer stem-like cell populations and promotes EMT in TRAMP PCa tumors(a) The protocol of TRAMP mice experiments was illustrated. TRAMP mice were castrated at 12-week-old. Tumor samples were collected and analyzed at 12wks, 16wks, 20wks, 24wks and 32wks. (b) The growth rates of prostate epithelium were demonstrated by BrdU incorporation in TRAMP prostate before and after castration. The mice were i.p. injected with BrdU (10 ug/g body weight) every 6hr, and killed 24hr later. Paraffin-fixed tissue sections were stained by the BrdU detecting kit (Zymed Laboratories). The castration decreased the BrdU incorporation rates in 16wks-old mouse prostates, while the BrdU incorporation rates began to increase from 20wks and even higher than pre-castration from about 24wks (P<0.05), indicating the happen of CRPC. (c) Considerable metastatic foci in lung kidney and liver of were gradually increased from 24-wk-castration TRAMP mice. (d) From 20wks to 24wks, the castration resistant tumor continually grew bigger in gross (the first and second upper row). H&E staining showed that castration resistant tumors are poorly differentiated from 16wks to 24wks tumor samples (the third row). When double staining CK5 (green, marker for basal epithelial cell) and CK8 (red, marker for luminal epithelial cell) in immunofluorescence examination, the decreasing CK8+ staining following castration were detected, and the increasing CK5+/CK8+(yellow color, overlapped by green and red signals) cells, which indicated the expansion of intermediate cell population, were noticed in 16wks and 20wks tumors (the fourth row). Interestingly, the staining for epithelial markers, both CK5 and CK8, was significantly diminished in 24wks tumors. The CD44 expression significantly increased in 20wks and 24wks of castration resistant tumors (the fifth row). And the expression of E-Cadherin significantly decreased in 20wks and 24wks of castration resistant tumors (the last row). Significance was defined as p<0.05(*). (e) To summarize the sequential events following castration. After the TRAMP mice were castrated in 12wks, the dedifferentiation of epithelium, characterized by expanded CK5+/CK8+ cell population, happened in 16wks, followed by the EMT transition on 20wks and metastasis on 24wks.
Mentions: In our TRAMP mouse model, mice were castrated at 12-weeks-old and tumor samples were collected at 16wks, 20 wks, 24wks, 28wks (Fig. 2a). We found that the proliferation marker, BrdU (and therefore, the growth rate too) was gradually increased from 16 wks tumors treated with ADT-castration to 32 wks tumor treated with ADT-castration castration tumor (Fig. 2b). In contrast, we found enhanced metastasis with more and more metastatic foci in liver, lung and kidney emerged from 24 wks tumor treated with ADT with castration (Fig. 2c).

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