Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy.

Much effort has been made to increase the survival rate of cancer patients through the development of early disease detection and the improvement of prognoses to guide appropriate therapeutic interventions. Although these strategies have improved survival rates significantly in cancer patients, the current prognostic and predictive markers used to determine treatment strategy remain insufficiently accurate in forecasting the outcome of individual patients. Because cancers are highly heterogeneous diseases, there often are exceptions to the current prognostic criteria, leading to the under treatment or over treatment of patients.1,2 Oncogenesis and cancer progression are complex processes involving a combination of many genetic and epigenetic insults. Cells undergo extensive biochemical and structural alterations during the process of malignant transformation because of these insults. Recent advances in cellular and molecular techniques have fostered a better understanding of the specific genetic and epigenetic changes that take place during cancer development and progression. From these changes, a large number of molecular tumor markers have been identified; however, only a few them have been shown to be reproducible and clinically relevant.3,4 In addition, most molecular markers are developed for specific types of tumors, thus allowing only a small portion of cancer patients to benefit from each type of marker. Phenotypic markers, such as histologic grading and staging, have been very useful tools for indicating the progression of cancer across a broad range of tumor types; however, these markers have limited prognostic capabilities, because there are often exceptions to the generally accepted trends of disease progression and inconsistent scoring of samples.5,6 Therefore, an easily detectable phenotypic marker that can be scored accurately and precisely in a broad range of tumor types would be ideal to increase the accuracy of prognosis for many cancer patients. In the current study, we describe the potential for developing the perinucleolar compartment (PNC) into such a prognostic marker. The PNC is a nuclear substructure that is associated with, but structurally distinct from, the nucleolus (Fig. 1A).7 The PNC is a generally heritable trait, and the structure is stable through interphase, disassembles during mitosis, and reassembles in early G1 phase.7 The PNC is concentrated with newly synthesized RNA polymerase III transcripts and RNA binding proteins,8–14 implicating the involvement of PNCs in RNA metabolism.15 However, the complete molecular composition and function of the PNC remain to be elucidated. Initial examination of the PNC in 13 human cell lines demonstrated that the PNC prevalence (the percentage of nonapoptotic and nonmitotic cells with 1 or more PNC) was invariably low in normal cell lines but was higher, yet hetrogenous, among cancerous and transformed cell lines,7 suggesting that the PNC forms preferentially in cancer cells. Investigations using human breast tissue samples demonstrated that PNC prevalence is 0% in normal breast epithelium, increases in parallel with disease progression (as determined by staging), and reaches nearly 100% in distant metastases, demonstrating that the PNC prevalence is associated with the malignancy of breast cancer. Multivariate analysis also demonstrated that PNC prevalence contains additional prognostic information over grading and tumor size for patients with stage I disease.16 FIGURE 1 Survey of perinucleolar compartment (PNC) prevalence (the percentage of cells with 1 or more PNC) in primary cells and cell lines. (A) Immunofluorescent staining of HeLa cells with a polypyrimide tract binding protein (PTB) antibody was used to mark the ... Although PNC prevalence has potential to be developed clinically as a prognostic marker for breast cancer,16 it is not clear whether the association of PNC prevalence with malignancy can be extended to tumors other than those originating in the breast. An association with malignancy in a broad range of tissue types would indicate that PNC prevalence has the potential to be a pancancer biomarker. To explore this possibility and to determine the specificity of the association between PNC and malignant behavior, we examined a large number of cells lines, primary cells, and human tumor samples derived from a broad spectrum of tissues for PNC prevalence and evaluated the selective association of PNC prevalence with metastatic capacity under various experimental conditions.