Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept.
There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of hu...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3082567?pdf=render |
| _version_ | 1818673170701352960 |
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| author | Soyoung Kim Shruti Goel Caroline M Alexander |
| author_facet | Soyoung Kim Shruti Goel Caroline M Alexander |
| author_sort | Soyoung Kim |
| collection | DOAJ |
| description | There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand-receptor pairs are separated into different cell types, and suggesting that Wnt-induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types. |
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| format | Article |
| id | doaj.art-66326301de7c453eb7870b20c4fd03bb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T07:51:32Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-66326301de7c453eb7870b20c4fd03bb2022-12-21T21:57:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0164e1931010.1371/journal.pone.0019310Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept.Soyoung KimShruti GoelCaroline M AlexanderThere is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand-receptor pairs are separated into different cell types, and suggesting that Wnt-induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types.http://europepmc.org/articles/PMC3082567?pdf=render |
| spellingShingle | Soyoung Kim Shruti Goel Caroline M Alexander Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. PLoS ONE |
| title | Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. |
| title_full | Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. |
| title_fullStr | Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. |
| title_full_unstemmed | Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. |
| title_short | Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. |
| title_sort | differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors proof of concept |
| url | http://europepmc.org/articles/PMC3082567?pdf=render |
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