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Interactions between cancer stem cells and their niche govern metastatic colonization



From Nature
By Stuart P. Atkinson

While metastatic tumour growth is the major cause of cancer mortality, this process is very inefficient for many cancers (Kouros-Mehr et al and Nguyen et al) and suggests that a barrier to implantation and growth exists to these few initiatory cancer cells mediated by the distant tissues in which they attempt to colonize. Further studies have demonstrated that metastases have prevalent target sites (Hess et al), again suggesting that normal tissue at the metastatic site may mediate colonisation. Now, researchers from the laboratory ofJoerg Huelsken at the École Polytechnique Fédérale De Lausanne (EPFL), Switzerland have shown that cancer stem cells (CSCs), or tumour initiating stem cells (TISCs), are vitally important in metastatic growth but this is reliant on complex interactions between the CSCs and their metastatic niche (Malanchi and Santamaria-Martínez et al).

This study aimed to elucidate factors mediating metastatic activity and the role of cancer stem cells (CSCs) using the MMTV-PyMT mouse breast cancer model, which is known to spontaneously metastasize to the lungs (Lin et al). CSCs from primary tumours and pulmonary metastases were identified with the markers CD90 (Thy1) and CD24, with CD24+CD29hi marking CSCs and CD24+CD49fhiidentifying normal gland stem cells. Separation of the CSCs from other cell types and transplantation demonstrated that only these cells were able to produce lung metastases and that during time course experiments, CSC number was positively correlated to metastatic colonisation. However, as the numbers of injected CSCs is significantly more than the number of metastatic tumours formed, it was surmised that additional factors, such as growth factors exuded from surrounding cells, or niche, may affect stem cell maintenance and proliferation. Postn, which encodes Periostin, was identified as a stromal factor of various normal stem cell niches through microarray RNA profiling studies comparing micro-dissected material from normal stem cells together with their adjacent stroma with micro-dissected material isolated from differentiated cells together with their adjacent stroma from the same tissue and further from the metastatic niche through RNA in situ hybridization in other tissues, in tumours and in metastases. Postn was shown to be produced by stromal Sma+Vim+ fibroblasts, induced in the lung stroma by infiltrating cancer cells but not in non-metastatic tumour-bearing alveolar lung tissue and also shown to be present in 75% of lymph node metastases in human breast cancer patients.

Upon analysis of breast cancers in MMTV-PyMT Postn-/- mice, the researchers found a dramatic decrease in number and size of pulmonary metastases, despite unaltered primary tumour size and morphology. However, upon transplantation of Postn-/- cells into WT mice, metastases were formed, suggesting that host stromal Postn expression determines metastatic efficiency.   Further analysis of how Postn is induced indicated a role for Tgfb3In silico promoter analysis showed that Smads may regulate Postn, CSCs and non-CSCs produced high levels of Tgfb3 and blocking Tgfb3 expression in tumour cells blocked Postn expression, as had been previously indicated (Muraoka et al). To further address Postn’s role in stem cell maintenance, growth of CSCs as neurospheres was assayed demonstrating that while Postn-deficient tumour cells could not form neurospheres, addition of the Periostatin protein to the media recovered this defect.

Interactome analysis with Postn was established to assess mechanisms that may control stem cell maintenance and confirmed “hits” included the Wnt ligands Wnt1 and Wnt3a and this association was shown to boost Wnt signalling activity. Interestingly, addition of Wnt3a rescued the in vitro stem cell expansion in the absence of Postn while FACS analysis found that Wnt signalling activity was concentrated on the CSC population. Using a lentiviral reporter which allows Wnt inducible GFP expression, it was shown that in the absence of Postn, Wnt signalling in metastases was abrogated. Additionally, Wnt target gene Axin2 was found at higher levels in wild type metastases compared to Postn-/- metastases and Wnt-driven breast cancers metastases was independent of stromal Postn.

Analysis of this model suggests that selective expansion of CSCs is responsible for the initiation of metastasis, that stromal production of Postn supports CSC growth and metastatic efficiency and colonisation, that CSCs signalling, through Tgfb3, is required to allow the host stroma to support metastasis initiation through Postn induction and that this promotes stem cell maintenance and metastatic colonization through the augmentation of Wnt signalling. Thorough knowledge of these types of interactions may allow therapeutic intervention to inhibit many types of metastatic cancers and may reduce cancer mortality.



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