Abstract
BackgroundThe aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression. For example, neuroendocrine differentiation is found more commonly in cancers destined to progress, including prostate and lung. We sought to identify proteins which are involved in neuroendocrine differentiation and differentially expressed in aggressive/metastatic tumours.ResultsExpression arrays were used to identify up-regulated transcripts in a neuroendocrine (NE) transgenic mouse model of prostate cancer. Amongst these were several genes normally expressed in neural tissues, including the pro-neural transcription factors Ascl1 and Hes6. Using quantitative RT-PCR and immuno-histochemistry we showed that these same genes were highly expressed in castrate resistant, metastatic LNCaP cell-lines. Finally we performed a meta-analysis on expression array datasets from human clinical material. The expression of these pro-neural transcripts effectively segregates metastatic from localised prostate cancer and benign tissue as well as sub-clustering a variety of other human cancers.ConclusionBy focussing on transcription factors known to drive normal tissue development and comparing expression signatures for normal and malignant mouse tissues we have identified two transcription factors, Ascl1 and Hes6, which appear effective markers for an aggressive phenotype in all prostate models and tissues examined. We suggest that the aberrant initiation of differentiation programs may confer a selective advantage on cells in all contexts and this approach to identify biomarkers therefore has the potential to uncover proteins equally applicable to pre-clinical and clinical cancer biology.
Highlights
The aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression
Malignant prostatic tumours commonly contain scattered or focal neuroendocrine type cells, but only a small minority or prostate cancers contain an homogenous population of such cells, when they are classified as small cell prostatic carcinoma
To do this we interrogated an expression array dataset from a prostate-specific Cre-LoxP p53PE-/-; RbPE-/mouse model of prostate cancer which has neuroendocrine characteristics and which maintains androgen receptor expression [15] (Figure 1)
Summary
The aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression. Neuroendocrine differentiation is found more commonly in cancers destined to progress, including prostate and lung. We sought to identify proteins which are involved in neuroendocrine differentiation and differentially expressed in aggressive/metastatic tumours. In recent years there has been much effort to identify new prostate cancer biomarkers. Malignant prostatic tumours commonly contain scattered or focal neuroendocrine type cells, but only a small minority or prostate cancers contain an homogenous population of such cells, when they are classified as small cell prostatic carcinoma. Some previous studies have failed to find convincing correlations between focal NE differentiation and prostate cancer progression [5,6,7] Variations in expression and detection of neuron-specific enolase, chromogranin A and synaptophysin may be partly responsible for this controversy. Better markers for a neural or neuroendocrine phenotype would benefit the field
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