Intersection of Brain Development and Paediatric Diffuse Midline Gliomas: Potential Role of Microenvironment in Tumour Growth

Loveson, Katie F.; Fillmore, Helen L.

doi:10.3390/brainsci8110200

Cited by 13 publications

(22 citation statements)

References 111 publications

(165 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although information on DIPG invasion routes is limited, perivascular spread has been observed in patient autopsy material (89). Considering the discrete temporal pattern of DIPG progression during brain development, it is conceivable that highly specific signals involved in brain development contribute to DIPG invasion, but this remains to be investigated (90). Moreover, DIPG's specific location plays a role as well with the pontine environment presenting a critical factor.…”

Section: Dipg Follows Preferred Routes For Invasionmentioning

confidence: 99%

“…This indeed resulted in reduced spread to the SVZ, establishing PTN as a critical neuron progenitor cell derived factor implicated in DIPG invasion (93) (Figure 2D), and further stressing the role of the brain microenvironment in this process. In this regard, it is again important to consider that the microenvironment and signaling molecules influencing DIPG are different from the adult brain, due to the temporal origin of DIPG in the still developing brain of pediatric patients (90).…”

Section: Specific Spread Into the Subventricular Zonementioning

confidence: 99%

“…Evidently, these culture models lack important cellular context that is present in vivo, including the tumor microenvironment that has such a strong impact on tumor cell behavior (127). This is even more relevant in the context of DIPG, given its unique origin in the pons during brain development (90). DIPG's spatiotemporal progression will therefore encounter very unique environmental conditions and signals that can have a specific impact on tumor cell behavior.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

See 2 more Smart Citations

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

View full text Add to dashboard Cite

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.

show abstract

Section: Dipg Follows Preferred Routes For Invasionmentioning

confidence: 99%

Section: Specific Spread Into the Subventricular Zonementioning

confidence: 99%

Section: Conclusion and Future Perspectivementioning

confidence: 99%

See 1 more Smart Citation

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…3) Surgical procedures are not suitable for the treatment of FOP because the resulting trauma causes a far more serious HO. 2,4) Thus, there are limited therapeutic options for FOP patients, 5) and there is a need for the development of pharma-ceutical agents for prevention and treatment, which requires further explanation of the underlying molecular drivers and causes of the disease.…”

Section: Introductionmentioning

confidence: 99%

ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma

2020

View full text Add to dashboard Cite

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

show abstract

“…In the 2016 World Health Organization (WHO) classification of central nervous system tumors, the more common malignant version of DIPG was reclassified as DMG, H3K27M due to the consistent discovery of K27 mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene. Although there are significant physiological and epidemiological differences, GB, DMG, and DIPG are all WHO Grade IV tumors of astrocytic origin with a highly malignant nature and a diffuse infiltrative growth pattern [3]. Pathological grade by the WHO 2007 criteria do not predict survival in H3K27M mutated gliomas [4].…”

Section: Introductionmentioning

confidence: 99%

A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen

Kast¹,

Michael

Sardi

et al. 2020

Brain Sciences

View full text Add to dashboard Cite

Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX’s transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session—the 5aai regimen—is warranted.

show abstract

Intersection of Brain Development and Paediatric Diffuse Midline Gliomas: Potential Role of Microenvironment in Tumour Growth

Cited by 13 publications

References 111 publications

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma

A New Treatment Opportunity for DIPG and Diffuse Midline Gliomas: 5-ALA Augmented Irradiation, the 5aai Regimen

Contact Info

Product

Resources

About