1. Wiley, Frieda PharmD

Article Content

Numerous factors can complicate cancer treatment. In the case of glioblastoma, intratumoral heterogeneity proves one of the greatest complexities in this tumor type because it demands more intricate, multi-faceted treatment approaches. The nuanced nature of gliomas warrants the need for research to identify active targets capable of disrupting tumor progression. New research appears to have accomplished this task through a comprehensive spatiotemporal study (Nat Commun 2022;

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However, to fully unravel the potential of novel therapies targeting this highly aggressive tumor type, one must first uncover additional details regarding the nature of the gliomas and the circumstances that contribute to their malignancy.


Previous studies have evaluated tumor motility and behavior of malignant cells at the glioma's invasive border without regard to motility of glioma cells at the tumor's core. This is the first study to oppose the general consensus that cells in the tumor's central core lack motility while exploring collective migratory patterns of malignant cells. Based on this hypothesis alone, an affirmative finding would indicate that glioma cell proliferation results from a combination of the tumor's activity at the invasive border and the ability of malignant cells to mobilize throughout the tumor into the normal brain.


Moreover, existing studies have identified collagen 1A1 (COL1A1) as a major component of the extracellular matrix in various cancers, including glioma. The protein has also been linked to growth and invasion. Data indicate that collagen fibers either resist tumor infiltration by creating passive, physical barriers, or support tumor cell migration with biochemical or biophysical activity.


To that end, some data inversely correlate COL1A1 density to patient prognosis in glioma. However, opposing studies draw an association between increased or decreased collagen deposition and increased tumor malignancy. For that reason, the authors of this study sought to elucidate how COL1A1 contributes to glioma cell proliferation-a concept that first requires one to understand the nature of malignancy in glioma cancers and heterogenous tumors.


Study Details

Characterized by a density reflective of tumor aggressiveness in genetically engineered murine glioma models and high-grade human gliomas, the regular, distinctive, anatomical multicellular fascicles exhibit spindle-like cells with aligned and elongation presentation. The study's authors refer to this trait as oncostreams.


These oncostreams illuminate the intratumoral distribution and are found both at the heart of the tumor as well as in the normal brain. These unique cells convey important information regarding how malignant glioma cells overtake an otherwise healthy brain.


In particular, high-grade gliomas (HGG) exhibit a volatility that earns them the title of being the most prevalent and malignant of brain tumors. These cancers quickly metastasize, overtaking normal, healthy brain tissue in their vicinity. Even though therapies exist, they offer limited hope, as noted by the tumors' frequent resistance to treatment and potential for recurrence within 12 months of therapy.


The skittish nature of HGG owes its heterogenous display to its histology, cell makeup, and molecular characterization. Pathologically, this translates to features such as pseudopalisades, microvascular proliferation, necrosis, and hypoxia. In addition, heterogeneity gives rise to malignancy in glioma, playing a role in resistance.


Three signatures tend to dictate the glioma's pathogenesis and often a prognosis. These are proenural, mesenchymal, and classical. For example, gliomas presenting with mesenchymal molecular signature typically exhibit highly aggressive histological traits such as hypoxic, necrotic, and microvascular proliferative regions-features that translate to a grimmer prognosis. Despite the predictive outcome correlation, researchers believe deriving greater clinical relevance in terms of prognosis lies in the characterization of the mesenchymal and its activity.


In fact, the hallmark of glioma is mesenchymal transformation. The spindle-like, fibroblast-like traits of mesenchymal cells exhibit a morphology that ultimately gives rise to cellular migration and invasion. Several factors dictate the mesenchymal phenotype. These include various transcription factors and downstream genes associated with the extracelullar matrix, cell adhesion, migration, and tumor angiogeneis.


During mesenchymal transformation, cells undergo biochemical and morphological changes that enable glioma cells to traverse the tumor environment and invade normal brain tissue. Tumor cell proliferation does not stop there. Malignant cells attack other healthy tissue, migrating along blood vessels, white matter, and subpial surface.


Tumor cells that present with a mesenchymal phenotype exhibit a special feature. Characterized by spindle-like morphology, they have a dynamic cell organization that enhances cell migration and invasion.


Researchers involved in this study found that malignant gliomas in HGG and mouse glioma models exhibit regular distinctive anatomical fascicles. By analyzing the mechanisms through which oncostreams are organized, scientists discovered that mesenchymal transformation signature enriched in extracellular matrix-related proteins defines oncostreams. This finding strongly suggests that COL1A1 is a major dictator of oncostream organization.


Furthermore, inhibiting the COL1A1 gene found within glioma cells results in oncostream loss and reshapes the HGG phenotype. More specifically, these findings suggest that COL1A1 helps dictate the tumor microenvironment scaffold and organizes areas of collective motion in the gliomas.


By using genetically engineered tumors exhibiting different malignant activities within a modeling system, researchers were able to replicate malignant histopathologies found in previous studies. They focused on two genotypes. The first genotype was activation of the RIK/RAS/PI3k pathway in combination with P53 and ATX downregulation. The second genotype was activation of RIK/RAS/PI3k with ATRX downregulation and expression of mutant IDH-RI32.


Through these findings, researchers found oncostream density to positively correlate with tumor aggressiveness as well as poor prognosis in both human and murine gliomas. Multicellular oncostream fascicles found in ex vivo and in vivo glioma models may promote tumor cell invasion, resulting in tumor aggressiveness.


One limitation of the study lies in the inability of intravital imaging to evaluate the interactions occurring between tumor cells, and individual cells of the normal brain. Another deficit is the ability to evaluate the significance the study's data bears on the migratory nature of human gliomas.


To expand their initial findings, the study's authors express the need for new strategies that use human explant models and characterize oncostream migration, as well as activity within the parenchyma of the normal brain.


Frieda Wiley is a contributing writer.