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The secreted cytokine osteopontin ( OPN ) was overexpressed by an average of threefold in metastatic tumours. Antibodies can block this

Very new but another possibility


Seed or soil?

Kristine Novak

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There is an ongoing debate as to whether the metastatic potential of a cancer cell is already present in the primary tumour, or whether it is acquired by cancer cells after they have broken free. A gene-expression profile analysis performed by Quin-Hai Ye et al., coupled with a supervised machine learning algorithm, has generated a molecular signature that indicates the former, and can be used to detect primary hepatocellular carcinomas (HCC) with metastatic potential. This approach could therefore be used to identify patients with HCCs that are most likely to metastasize.

Ye et al. compared gene-expression profiles of 50 primary and metastatic HCC samples from 30 patients whose tumours had or had not metastasized. Unexpectedly, the gene-expression profiles of primary and matched metastatic HCCs were not very different. Primary tumours that had not metastasized, however, had a gene-expression profile that was quite different from that of primary HCCs that had undergone metastasis. This means that metastatic tumours have a similar gene-expression signature to their parent tumour, whereas metastasis-free HCCs are distinct from metastatic primary HCCs. The metastatic gene signature was independent of tumour size, tumour encapsulation or patient age. So, metastatic potential seems to be pre-determined in primary HCCs.

To define a gene set that could accurately be used to predict which patients' HCCs were most likely to metastasize, the authors used a 'supervised machine learning' classification algorithm known as compound covariate predictor, which includes a cross-validation test to avoid overestimation of prediction accuracy. This strategy correctly predicted 90% of primary tumours that would become metastatic, and the prediction outcome was correlated with patient survival.

So, what genes are upregulated by metastatic HCC? The secreted cytokine osteopontin ( OPN ) was overexpressed by an average of threefold in metastatic tumours. This gene is also overexpressed in metastatic breast tumours, and malignant lung, colon and prostate cancers. HCC cell lines were also found to express high levels of this protein, and the authors showed that antibodies against OPN could block HCC metastasis to the lung in nude mice. Because increased OPN levels can be detected in the plasma of cancer patients, it might make a good diagnostic marker, as well as a therapeutic target.

The finding that the HCC metastatic programme is initiated in the primary tumour indicates that analysis strategies such as these can also be used to identify patients with pre-metastatic tumours. This predictor, however, awaits confirmation from larger independent data sets. Furthermore, all the HCC samples in this study were obtained from hepatitis-B-virus-positive Chinese patients, so this model must be tested in other populations, including those with hepatitis-C-virus-related HCC.

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