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Cancer stem cell theory: pathologists’ considerations and ruminations about wasting time and wrong evaluations
  1. P Nuciforo1,
  2. F Fraggetta2
  1. 1Fimo-Firc Institute of Molecular Pathology, Via Adamello 16, Milano 20139, Italy;
  2. 2Azienda Ospedaliera Cannizzaro, Via Messina, 829, Catania 95126, Italy

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    The genomic revolution has changed the role of the pathologist. In daily practice, our work is no longer limited to reaching a correct diagnosis and we are asked to answer questions about the patient’s prognosis and treatment options through the evaluation of selected molecular targets (such as erbB2 for breast cancer) in tumour specimens. Thus, we have acquired a major role in the translation of novel gene findings from experimental model systems to their clinical application.

    There is overwhelming evidence that only a subset of cells within a tumour clone, referred to as cancer stem cells, are tumorigenic and possess the metastatic phenotype.1 The recent identification of human breast cancer initiating cells by Al-Hajj and colleagues2 provided a major step forward in this field. With this knowledge, the stem cell compartment should represent the selected target for tumour eradication.

    As pathologists we would like to share some considerations and ruminations about this scenario.

    Currently, tissue microarray analysis generates gene profiles capable of differentiating tumours with different biological behaviours.3 However, this screening method is conducted on heterogeneous tumour tissue samples containing a mixture of non-neoplastic cells, non-tumorigenic cancer cells, and cancer stem cells. Similarly, until now, we have evaluated the immunohistochemical expression of a molecular marker in the bulk of the tumour, considering it as relatively homogeneous.

    What is the clinical relevance of these results? Although new therapeutic approaches based on these studies have modified the prognosis of some neoplasms,4 conflicting results are still seen with many other tumours.5 We should start to feel worried about the value of the information retrieved from this type of tumour analysis.

    The few cancer stem cells and the large number of cells constituting the tumour are morphologically similar but functionally heterogeneous. It is likely that we are still evaluating the main population of tumour cells, which are not cancer stem cells, and are thus probably wasting time and loosing essential treatment information. It is unlikely that gene expression profiles obtained using the currently available methods reflect those of the tumour stem cell population, which forms only 0.1–2% of the whole tissue sample.1,2,6

    The cancer stem cell hypothesis has started a new era in cancer research. Tumours contain functionally different subpopulations of cells. However, unique gene expression profiles are generated by current methods of evaluation. Probably, when the isolation and molecular characterisation of cancer stem cells from primary tissue becomes possible, the role of pathologists will change again. Collaboration between researchers and pathologists will be more widely practised and we will be able to rise to the next challenge; namely, assessing the prognosis of a patient from only one of 5000 tumour cells in a tissue sample.