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ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma.

Phi JH, Choi SA, Lim SH, Lee J, Wang KC, Park SH, Kim SK - BMC Cancer (2013)

Bottom Line: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers.The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo.High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.

ABSTRACT

Background: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma.

Methods: ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels.

Results: Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas.

Conclusions: High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma.

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ID3 knockdown by shRNA and inhibition of tumor seeding in vivo. (A) Representative live in vivo imaging of implanted D283 cells transfected with either control-shRNA or ID3-shRNA for 28 days. Note the migration of signals along the spinal cord of a mouse injected with D283-control-shRNA. (B) Serial measurement of tumor-occupied areas in live in vivo imaging. (C) Serial measurement of the longitudinal extent of tumors from the cranium to the spinal canal. (D) Representative gross photos of mice injected with PBS, D283-controlshRNA, and D283-ID3-shRNA. Mice that received D283-control-shRNA (middle photo) show cachexia and scoliosis, signs of tumor seeding along the spinal cord. (E) A Kaplan-Meier survival plot of mice after implantation of D283 cells reveals the increased survival by shRNA. All animals were sacrificed at day 28 for histological examination.
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Figure 4: ID3 knockdown by shRNA and inhibition of tumor seeding in vivo. (A) Representative live in vivo imaging of implanted D283 cells transfected with either control-shRNA or ID3-shRNA for 28 days. Note the migration of signals along the spinal cord of a mouse injected with D283-control-shRNA. (B) Serial measurement of tumor-occupied areas in live in vivo imaging. (C) Serial measurement of the longitudinal extent of tumors from the cranium to the spinal canal. (D) Representative gross photos of mice injected with PBS, D283-controlshRNA, and D283-ID3-shRNA. Mice that received D283-control-shRNA (middle photo) show cachexia and scoliosis, signs of tumor seeding along the spinal cord. (E) A Kaplan-Meier survival plot of mice after implantation of D283 cells reveals the increased survival by shRNA. All animals were sacrificed at day 28 for histological examination.

Mentions: Live in vivo imaging of the mice injected with only PBS (N = 3) or with D283-control-shRNA (N = 7) revealed an enlargement of tumor masses at the injection site for 21 days and seeding along the spinal cord thereafter. In contrast, the mice injected with D283-ID3-shRNA (N = 6) exhibited stable tumor mass sizes at the injection site and no seeding along the spinal cord (Figure 4A). A significant difference in the total areas of optical signal between the groups (D283-control-shRNA vs. D283-ID3-shRNA) was observed (P = 0.028; ANOVA; Figure 4B). The longitudinal length of the optical signals from the cranium to the spinal canal was also significantly different between groups (P < 0.001; ANOVA; Figure 4C).


ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma.

Phi JH, Choi SA, Lim SH, Lee J, Wang KC, Park SH, Kim SK - BMC Cancer (2013)

ID3 knockdown by shRNA and inhibition of tumor seeding in vivo. (A) Representative live in vivo imaging of implanted D283 cells transfected with either control-shRNA or ID3-shRNA for 28 days. Note the migration of signals along the spinal cord of a mouse injected with D283-control-shRNA. (B) Serial measurement of tumor-occupied areas in live in vivo imaging. (C) Serial measurement of the longitudinal extent of tumors from the cranium to the spinal canal. (D) Representative gross photos of mice injected with PBS, D283-controlshRNA, and D283-ID3-shRNA. Mice that received D283-control-shRNA (middle photo) show cachexia and scoliosis, signs of tumor seeding along the spinal cord. (E) A Kaplan-Meier survival plot of mice after implantation of D283 cells reveals the increased survival by shRNA. All animals were sacrificed at day 28 for histological examination.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 4: ID3 knockdown by shRNA and inhibition of tumor seeding in vivo. (A) Representative live in vivo imaging of implanted D283 cells transfected with either control-shRNA or ID3-shRNA for 28 days. Note the migration of signals along the spinal cord of a mouse injected with D283-control-shRNA. (B) Serial measurement of tumor-occupied areas in live in vivo imaging. (C) Serial measurement of the longitudinal extent of tumors from the cranium to the spinal canal. (D) Representative gross photos of mice injected with PBS, D283-controlshRNA, and D283-ID3-shRNA. Mice that received D283-control-shRNA (middle photo) show cachexia and scoliosis, signs of tumor seeding along the spinal cord. (E) A Kaplan-Meier survival plot of mice after implantation of D283 cells reveals the increased survival by shRNA. All animals were sacrificed at day 28 for histological examination.
Mentions: Live in vivo imaging of the mice injected with only PBS (N = 3) or with D283-control-shRNA (N = 7) revealed an enlargement of tumor masses at the injection site for 21 days and seeding along the spinal cord thereafter. In contrast, the mice injected with D283-ID3-shRNA (N = 6) exhibited stable tumor mass sizes at the injection site and no seeding along the spinal cord (Figure 4A). A significant difference in the total areas of optical signal between the groups (D283-control-shRNA vs. D283-ID3-shRNA) was observed (P = 0.028; ANOVA; Figure 4B). The longitudinal length of the optical signals from the cranium to the spinal canal was also significantly different between groups (P < 0.001; ANOVA; Figure 4C).

Bottom Line: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers.The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo.High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.

ABSTRACT

Background: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma.

Methods: ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels.

Results: Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas.

Conclusions: High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma.

Show MeSH
Related in: MedlinePlus