Browsing by Author "Grigore, Alexandru Dan"

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    Prostate cancer and neuroendocrine differentiation: more neuronal, less endocrine?
    (Frontiers Media S.A., 2015) Grigore, Alexandru Dan; Ben-Jacob, Eshel; Farach-Carson, Mary C.; Center for Theoretical Biological Physics
    Neuroendocrine differentiation (NED) marks a structural and functional feature of certain cancers, including prostate cancer (PCa), whereby the malignant tissue contains a significant proportion of cells displaying neuronal, endocrine, or mixed features. NED cells produce, and can secrete, a cocktail of mediators commonly encountered in the nervous system, which may stimulate and coordinate cancer growth. In PCa, NED appears during advanced stages, subsequent to treatment, and accompanies treatment resistance and poor prognosis. However, the term "neuroendocrine" in this context is intrinsically vague. This article seeks to provide a framework on which a unified view of NED might emerge. First, we review the mutually beneficial interplay between PCa and neural structures, mainly supported by cell biology experiments and neurological conditions. Next, we address the correlations between PCa and neural functions, as described in the literature. Based upon the integration of clinical and basic observations, we suggest that it is legitimate to seek for true neural differentiation, or neuromimicry, in cancer progression, most notably in PCa cells exhibiting what is commonly described as NED.
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    Reassessment of Neurite-Like Processes in a Neuroendocrine Prostate Cancer Model
    (2020-06-03) Grigore, Alexandru Dan; Farach-Carson, Mary C.; Levine, Herbert; Carson, Daniel D.
    Neuroendocrine differentiation (NED) is a constellation of histological and functional features of certain cancer types, including prostate cancer (PCa), whereby a fraction of tumor cells display neuronal and endocrine features. Unlike patients with conventional PCa, whose tumors show a pure population of tumor cells expressing epithelial markers, patients with NED also show a subpopulation of tumor cells expressing neuroendocrine (NE) lineage markers. NED can be induced by various factors, including therapy (which further explains the association between NED and therapy resistance) and paracrine factors secreted by bone marrow stromal cell lines (which suggests that NED might be important for PCa metastasis to bone). When NED is induced in vitro, the cultured PCa cells not only show NE lineage markers but also NE lineage morphology, which is characterized by neurite-like processes. However, despite the fact that NED has been studied for several decades, the precise nature of these processes remains unclear and the term itself is thus inherently vague. This work aimed to assess the overlap between PCa NED and true neuronal phenotype. Literature search was conducted to construct a battery of pan-neuronal markers, which were assessed in NED cells in vitro by immunocytochemistry (ICC). The presence of only two core pan-neuronal markers (partly overlapping with therapy resistance) coupled with the absence of other critical pan-neuronal markers suggested that NED cells did not display a true neuronal phenotype. However, the morphology of neurite-like processes showed similarities to tunneling nanotubes (TNTs). TNTs are recently described, cytoskeletal filament-containing intercellular bridges which are involved in cell-cell trafficking of various particles ranging from cytosolic proteins to viruses and mitochondria. Time-lapse imaging, co-culture with bone marrow stromal cells, carbocyanine dye transfer, and cytoskeletal live staining were performed on NED cells in vitro, which collectively suggested that neurite-like processes mediated formation of TNT connections between NED cells. Analysis of gene expression profiles of NED was conducted using data derived from this group’s previous work as well as publicly available databases, and a set of candidate genes potentially important for TNT formation in NED cells was constructed. Most upregulated genes in the gene set were also highly expressed in brain, and several were involved in cytoskeletal organization, including neurite formation or maintenance. The expression of the corresponding proteins was assessed in NED cells in vitro by ICC, and a subset thereof was further assessed in human PCa tissue samples by immunohistochemistry-immunofluorescence (IHC-IF). Collectively, these findings suggest that NED cells do not adopt a true neuronal phenotype, but rather use subroutines of the neuronal program for extending neurite-like processes, which then mediate establishment of TNT connections.
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    Tumor Budding: The Name is EMT. Partial EMT.
    (MDPI, 2016) Grigore, Alexandru Dan; Jolly, Mohit Kumar; Jia, Dongya; Farach-Carson, Mary C.; Levine, Herbert; Center for Theoretical Biological Physics; Systems, Synthetic, and Physical Biology Program
    Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the vast heterogeneity in its exact definition, methodology of assessment, and patient stratification need to be resolved before it can be routinely used as a standardized prognostic feature. Here, we discuss the heterogeneity in defining and assessing tumor budding, its clinical significance across multiple cancer types, and its prospective implementation in clinical practice. Next, we review the emerging evidence about partial, rather than complete, epithelial-mesenchymal phenotype at the tumor bud level, and its connection with tumor proliferation, quiescence, and stemness. Finally, based on recent literature, indicating a co-expression of epithelial and mesenchymal markers in many tumor buds, we posit tumor budding to be a manifestation of this hybrid epithelial/mesenchymal phenotype displaying collective cell migration.