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Expression profile analysis reveals that the microRNA signatures change at distinct stages of tumorigenesis.
Do microRNA (miRNA) expression profiles reflect specific stages in tumour progression? Douglas Hanahan and colleagues set out to answer this question by analysing the miRNA transcriptome in distinct stages of tumorigenesis in the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumours (PNETs).
Normal, hyperplastic and angiogenic islets, primary tumours and liver metastases from RIP1-Tag2 mice were profiled for expression of all known mouse miRNAs, and this revealed that each stage had specific differences in miRNA expression. Interestingly, several of the miRNAs upregulated in hyperplastic and angiogenic islets are known to be expressed in haematopoietic cells, and the authors confirmed that the increased expression of these miRNAs corresponded to an increase in immune cell infiltration rather than a change to the expression in tumour cells.
By comparing primary tumours and liver metastases, the authors discovered that a small subset of primary tumours had an miRNA signature that was similar to metastases rather than to other primary tumours. It is possible that these 'metastasis-like' primary PNETs represent tumours that are more likely to metastasize, and therefore the propensity to metastasize may be determined early in tumorigenesis. Decreased expression of the miR-200 family of miRNAs, leading to the loss of E-cadherin expression through the increased expression of the transcriptional repressor ZEB1, was substantial in both metastasis-like primary tumours and metastases.
The authors also asked whether the miRNA signature of angiogenic islets could be normalized by pharmacological inhibition of angiogenesis. Treatment of RIP1-Tag2 mice with sunitinib reduced the expression of miRNAs upregulated in the angiogenic signature, and the authors found that changes in miRNA expression levels reflected a decrease in the relative proportions of endothelial cells, pericytes and inflammatory cells present in tumours following treatment. In response to sunitinib, many tumours acquired an miRNA profile similar to that of metastases, supporting previous studies suggesting that adaptive resistance to angiogenesis inhibitors may involve increased metastasis.
Do mouse PNETs resemble human tumours? The comparison of normal human islets, PNETs and liver metastases to mouse profiles showed that a subset of miRNAs are similarly regulated between species, and the authors propose that these cross-filtered miRNAs are most likely to have functional roles in PNET progression. Furthermore, many of the miRNAs altered in mouse PNETs were also altered in other human tumour types, indicating that similar changes in miRNA expression are often selected for during tumorigenesis irrespective of tissue type.
