Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5 Journal Article
| Authors: | Xu, X.; Lee, T. C.; Offor, N.; Cheng, C.; Liu, A.; Fang, Y.; Jhanwar, S. C.; Abramson, D. H.; Cobrinik, D. |
| Article Title: | Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5 |
| Abstract: | Retinoblastomas consist of cone-like neoplastic cells and diverse non-neoplastic cells whose roles in tumorigenesis have not been defined. Here, we investigated the glial cells that constitute 2% to 3% of the cells in retinoblastoma tumors, including their origin, their relationship to a potential retinoblastoma stem cell population, and their effects on tumor cell proliferation. Retinoblastoma glia consistently expressed the retinal astrocyte marker Pax2 but inconsistently expressed the Müller cell and occasional astrocyte marker CRALBP. Many of the glia expressed the stem cell-associated Sox2 but nevertheless were non-neoplastic as they coexpressed Rb and/or retained two RB1 alleles. Conversely, the glia were distinct from the non-neoplastic cells that strongly expressed the stem cell-associated ABCG2. Adherent Pax2 +,Sox2+,Rb+ glia readily grew from explanted retinoblastomas and produced soluble factors that enhanced the proliferation of cocultured retinoblastoma cells. This effect was emulated by normal retinal glia and appeared to be mediated by insulin-like growth factor binding protein-5 (IGFBP-5), as it was mimicked by recombinant IGFBP-5 and mitigated by neutralizing IGFBP-5 antibody. As glia-derived IGFBP-5 was earlier found to promote photoreceptor survival, our findings indicate that retinal astrocytes enhance the proliferation of cone-like retinoblastoma cells by deploying a factor that also provides trophic support to the tumor cells' non-neoplastic counterparts. These observations suggest that a tissue-specific microenvironmental feature cooperates with oncogenic mutations in a cancer cell of origin to promote retinoblastoma tumorigenesis. Copyright © American Society for Investigative Pathology. |
| Keywords: | controlled study; protein expression; gene mutation; nonhuman; cell proliferation; animal cell; mouse; allele; cell survival; astrocyte; retinoblastoma; cell population; carcinogenesis; stem cell; oncogene; breast cancer resistance protein; glia cell; retinoblastoma protein; transcription factor sox2; photoreceptor; transcription factor pax2; neutralizing antibody; somatomedin binding protein 5; mueller cell; retina cell |
| Journal Title: | American Journal of Pathology |
| Volume: | 177 |
| Issue: | 1 |
| ISSN: | 0002-9440 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2010-07-01 |
| Start Page: | 424 |
| End Page: | 435 |
| Language: | English |
| DOI: | 10.2353/ajpath.2010.090512 |
| PROVIDER: | scopus |
| PMCID: | PMC2893684 |
| PUBMED: | 20508032 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: AJPAA" - "Source: Scopus" |
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