జర్నల్ ఆఫ్ స్టెమ్ సెల్ రీసెర్చ్ & థెరపీ

నైరూప్య

Glioblastoma Stem Cells: Conversion or Reprogramming from Tumor Non- Stem Cells?

Davide Schiffer, Laura Annovazzi, Paola Cassoni, Maria Consuelo Valentini, Marta Mazzucco and Marta Mellai

It is widely accepted that gliomas origin from immature glia and the most important hypothesis is that this origin is from glioblastoma stem cells (GSCs). GSCs are responsible for tumor growth, proliferation, therapy resistance and recurrence. They may represent transformed normal neural stem cells (NSCs), embryonically regressed adult glia or, simply, a functional status that could be regulated by the tumor microenvironment. Objective of the work is to interpret all the immunohistochemical, genetic and in vitro culture features of primary tumors and cell lines in favor of the above mentioned hypothesis on the functional status and microenvironment. A series of glioblastomas (GBMs) have been studied after stereotactic biopsies for expression of stemness and differentiation antigens, genetic aberrations and stem cell generation potential by immunohistochemical, immunofluorescence, molecular genetics methods. Perivascular and perinecrotic niches are the crucial points where microenvironment exerts its influence. The most malignant regions of GBM contain hyperproliferating areas expressing stemness antigens, such as Nestin, SOX2, CD133 and almost no differentiation antigens and show a high proliferation index. Circumscribed necroses develop within these areas by ischemia due to the imbalance between the high proliferation rate of tumor cells and the low one of endothelial cells. Perinecrotic GSCs are interpreted as elicited by hypoxia through HIF-1/2 constituting thus a niche. The hypothesis can be formulated that the stem cell status is a functional one that can be reached by dedifferentiated tumor cells through embryonic regression and that GSCs surrounding circumscribed necroses may of course represent a niche, but they are the residue of GCSs/progenitors originally populating the hyperproliferating areas. A conversion of tumor non-stem cells into tumor stem cells is possible, as well as reprogramming of tumor cells due to the microenvironment regulation through its intrinsic and extrinsic signaling. This hypothesis could influence the therapeutic strategies addressed to annihilate GSCs.