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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 4  |  Page : 137-138

Scarring, without regeneration, is the therapeutic challenge for making palliative glioma treatments curative

Braintech Lab, INSERM UMR1205, Faculty of Medicine and Pharmacy, Grenoble Alpes University, La Tronche, France

Date of Submission09-Dec-2022
Date of Decision10-Jan-2023
Date of Acceptance10-Jan-2023
Date of Web Publication08-Mar-2023

Correspondence Address:
Dr. Didier Wion
Braintech Lab, INSERM UMR1205, Faculty of Medicine and Pharmacy, Grenoble Alpes University, La Tronche
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_28_22

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How to cite this article:
Chabrol T, Chin SM, Berger F, Wion D. Scarring, without regeneration, is the therapeutic challenge for making palliative glioma treatments curative. Glioma 2022;5:137-8

How to cite this URL:
Chabrol T, Chin SM, Berger F, Wion D. Scarring, without regeneration, is the therapeutic challenge for making palliative glioma treatments curative. Glioma [serial online] 2022 [cited 2023 Jun 4];5:137-8. Available from: http://www.jglioma.com/text.asp?2022/5/4/137/371291

A recent study published in Neuro-Oncology[1] shows an increase in pleiotrophin (PTN) expression following glioblastoma resection. This observation adds new evidence of the existence of the tumorigenic side effects of surgical resection.[2]

PTN, also known as Heparin-Binding Brain Mitogen and Heparin-Binding Growth Associated Molecule, has long been associated with regenerative healing. For example, PTN is a common contributor to the bone, muscle, and liver regeneration.[3] It also regulates the expansion and regeneration of hematopoietic stem cells.[4] The elevated level of PTN after tumor resection is, therefore, consistent with a tissue regenerative healing response to surgery injury; that will be the "tumor recurrence." Any treatment that does not consider this issue is condemned to be palliative, rather than curative.

Contrary to tumor tissues, most adult organs have limited regenerative potential. The endpoint of their healing process is the formation of a scar. In the brain, the glial scar creates the barrier that surrounds and isolates the lesion core. Perivascular and meningeal fibroblasts and pericytes make fibrotic scars that occur within lesion cores. The scarring process is a necessary contributor to brain healing.[5] The scar is not a consequence but a factor in the healing process. The formation of a mature glial scar takes several weeks to reach completion and requires the absence of exacerbating injury.[5] The spread of invasive cancer cells and therapy-induced tissue damages are such exacerbating injuries. A largely overlooked point is that although invasive brain tumors elicit reactive gliosis, they are not surrounded by a well-defined astrocyte or fibrotic scar.[5] The question arises as to why we have neglected to consider the resolution of the scarring process into a mature scar as a therapeutic imperative.

In the words of Hippocrates, "Medicine consists of adding and subtracting, subtracting what is in excess, adding what is deficient." In glioblastoma, the readily observable excess to subtract is the tumor mass. This may have led us to focus our therapeutic efforts on subtractive treatments such as tumor resection and killing cancer cells. To observe a deficiency like a scar defect is less straightforward. A deficiency is defined in reference to a control. Neither scar is observable in patients, nor in the normal nontrauma tissues used as controls in our studies. Scarring is an emergent function of tissues; a cell does not scar, but tissue does. Therefore, the observation of a mature scar is also not common in experimental cell culture studies. Moreover, once observed, dealing with a deficiency can be tricky. Tumor hypoxia is such an example. Even though hypoxia is a deficiency, we initially designed our anti-angiogenic strategy not to add but to subtract oxygen. As a result, the approach initially failed before we discovered its therapeutic interest to normalize the tumor vasculature, i.e., "in adding what is deficient." Indeed, we could restate Hippocrates' principle in "Medicine consists in normalization." A critical missing step in our therapeutic strategies is the normalization of the healing process through the formation of its endpoint, the functional scar. It is necessary to resolve this issue to make palliative therapies curative. Scars are borders, and history shows us that the restoration of borders may help to resolve conflicts and prevent invasions.



Financial support and sponsorship

The work is funded by Institut National de la Santé et de la Recherche Médicale.

Conflicts of interest

There are no conflicts of interest.

Editor note: DW is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

  References Top

Knudsen AM, Halle B, Cédile O, Burton M, Baun C, Thisgaard H, et al. Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors. Neuro Oncol 2022;24:1074-87.  Back to cited text no. 1
Hamard L, Ratel D, Selek L, Berger F, van der Sanden B, Wion D. The brain tissue response to surgical injury and its possible contribution to glioma recurrence. J Neurooncol 2016;128:1-8.  Back to cited text no. 2
Asahina K, Sato H, Yamasaki C, Kataoka M, Shiokawa M, Katayama S, et al. Pleiotrophin/heparin-binding growth-associated molecule as a mitogen of rat hepatocytes and its role in regeneration and development of liver. Am J Pathol 2002;160:2191-205.  Back to cited text no. 3
Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, et al. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 2010;16:475-82.  Back to cited text no. 4
Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014;81:229-48.  Back to cited text no. 5


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