Friday, February 24, 2012

Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:
Hi Brian,
I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.
Charles Eberhart, MD PhD
Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.


jd said...

I agree with Charles.

Joshua A Sonnen said...

Charles and Fausto put together a very convincing argument.

Anonymous said...

We have done some investigation into this, using fresh-frozen glioblastoma specimens as well as cultured cells and immunofluorescence/confocal microscopy. We have found some vessels in glioblastomas with cells which double-label for CD34 and glial markers, but these are a small minority of the vessels in the sections. So while I suspect that glioblastoma "stem cells" can form vascular structures, this is not normally a major component of the tumor vasculature. Now, what happens with blockade of VEGF with bevacizumab, I don't know.
(Doug Miller posting as "anonymous" as usual because Google won't accept the passwords they themselves gave me)

Anonymous said...

David Capper:
The data and interpretation fit well with our observations as diagnostic neuropathologists. We also did a small analysis of 10 secondary glioblastomas with IDH1 R132H mutations by immunohistochmistry and observed no positive cells in the vessels of9/10 cases. In one case we observed single IDH1 R132H positive cells (altogether approximately 5 cells) within the vessel wall but not forming part of the luminal surface.

Anonymous said...

While working in a brain tumor lab several years ago I reviewed IHC stains of cell pathway markers in GBMs and noted in some vessels tumor cells infiltrating the walls of blood vessels distinct from endothelium. I agree with Dr. Eberhart.

Anonymous said...

As a aspiring future neuropathologist, I'd like to share some of my opinion. My hypothesis is that there are at least 3 cells of origins for glioblastoma: NSC, OPC and blood vessels. For secondary GB, it is clear that they evolve from low-grade glioma over time which most like developed from glial progenitors. I think the secondary GB is less likely to possess the potential of endothelial transdifferentiation. However, it is possible that one kind of cell of origin for primary GB is endothelial origin which underwent endothelial-glial transformation. So this type of primary GB could still possess stemness of endothelial differentiation. So practicing neuropathologist should not draw generalized conclusion by only looking at some secondary GB.