Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma

Abstract

Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options.

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

“…In brain tumors (gliomas), a mechanism resembling EMT is responsible for therapy resistance and cancer recurrence. PMT is the shift of glioma stem-like cells (GSCs) of the proneural subtype to the more aggressive mesenchymal subtype 49 . PMT can be induced by radiation both in mice 24 and humans 25 .…”

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

“…Physiologically, EMT can be observed during embryogenesis, tissue development and wound healing [48]. It is also a common phenomenon during carcinogenesis and can either induce or coexist with various malignancies such as breast cancer, thyroid cancer, cholangiocarcinoma, non-small cell lung carcinoma, colorectal cancer, inflammatory bowel disease or GC [49][50][51][52][53][54][55][56][57][58][59][60]. During the EMT process, ECs undergo a series of biochemical reactions that eventually lead to alterations in the cells' morphology, especially the loss of the polarity of cells [17,61].…”

ZBTB18 inhibits SREBP-dependent fatty acid synthesis by counteracting CTBPs and KDM1A/LSD1 activity in glioblastoma

“…1E-G), further supporting ZBTB18-CTBP2 interaction. We then looked at phenotypic 7 changes associated with ZBTB18 or ZBTB18-mut expressions in SNB19 cells.…”

“…Gene expression studies have highlighted the existence of a mesenchymal phenotype associated with the most aggressive glioblastoma features such as invasion and therapy resistance (3)(4)(5)(6). Importantly, the acquisition of mesenchymal traits resembles the mesenchymal transition described in epithelial tumors and it is now considered a hallmark of aggressive tumors (7,8). Epigenetic changes in the cells are reversible covalent modifications which alter gene expression without changing the DNA sequence, and can be inherited by the cell progeny.…”