The complex aspects linking the nucleolus and ribosome biogenesis to cancer are reviewed here. The available evidence indicates that the morphological and functional changes in the nucleolus, widely observed in cancer tissues, are a consequence of both the increased demand for ribosome biogenesis, which characterizes proliferating cells, and the changes in the mechanisms controlling cell proliferation. In fact, the loss or functional changes in the two major tumor suppressor proteins pRB and p53 cause an up-regulation of ribosome biogenesis in cancer tissues. In this context, the association in human carcinomas of nucleolar hypertrophy with bad prognoses is worthy of note. Further, an increasing amount of data coming from studies on both hepatitis virus-induced chronic liver diseases and a subset of rare inherited disorders, including X-linked dyskeratosis congenita, suggests an active role of the nucleolus in tumorigenesis. Both an up-regulation of ribosome production and changes in the ribosome structure might causally contribute to neoplastic transformation, by affecting the balance of protein translation, thus altering the synthesis of proteins that play an important role in the genesis of cancer. (Am J Pathol

The importance of nucleolar changes in cancer cells is underestimated in tumour pathology. There is evidence that the nucleolus is the mirror of a series of metabolic changes that characterize cancer cells. Cell entry into the cell cycle is always associated with up-regulation of the nucleolar function and increased nucleolar size, which are also directly dependent on the rapidity of cell cycle progression. Furthermore, alterations of the major tumour suppressor retinoblastoma (Rb) and p53 pathways also contribute to the stimulation of nucleolar function and to nucleolar enlargement. High cell growth fraction, high cell growth rate and disruption of the Rb and p53 pathways are responsible for greater aggressiveness of cancer tissues. Therefore, the evaluation of nucleolar size allows one to obtain reliable information on the clinical outcome of the cancer: the greater the nucleolar size, the worse the tumour prognosis. Indeed, a series of studies carried out on numerous human tumours has shown that nucleolar hypertrophy (prominent nucleolus) was an independent predictive and prognostic parameter of a fatal clinical outcome.

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The structure and the function of interphase AgNORs and the importance of the "AgNOR" parameter in tumor pathology have been reviewed. Interphase AgNORs are structural-functional units of the nucleolus in which all the components necessary for ribosomal RNA synthesis are located. Two argyrophilic proteins involved in rRNA transcription and processing, nucleolin and nucleophosmin, are associated with interphase AgNORs and are responsible for their stainability with silver methods, thus allowing interphase AgNORs to be visulaized at light microscopic level, also in routine cyto-histopathological preparations. The number of interphase AgNORs is strictly related to rRNA transcriptional activity and, in continuously proliferating cells, to the rapidity of cell proliferation. Evaluation of the quantitative distribution of interphase AgNORs has been applied in tumor pathology both for diagnostic and prognostic purposes. The "AgNOR" parameter has been proved to represent a reliable tool for defining the clinical outcome of cancer disease, being an independent prognostic factor in many types of tumors.

Multifaceted relations link ribosome biogenesis to cancer. Ribosome biogenesis takes place in the nucleolus. Clarifying the mechanisms involved in this nucleolar function and its relationship with cell proliferation: (1) allowed the understanding of the reasons for the nucleolar changes in cancer cells and their exploitation in tumor pathology, (2) defined the importance of the inhibition of ribosome biogenesis in cancer chemotherapy and (3) focused the attention on alterations of ribosome biogenesis in the pathogenesis of cancer. This review summarizes the research milestones regarding these relevant relationships between ribosome biogenesis and cancer. The structure and function of the nucleolus will also be briefly described.