Cerebral cavernous malformation pathogenesis [Neurosurgery Wiki]

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====== Cerebral cavernous malformation pathogenesis ======
CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of [[MEKK3]]-[[KLF2]]/4 signaling in [[vascular]] [[endothelial cell]]s. Gain-of-function mutations in [[PIK3CA]] (encoding the enzymatic subunit of the [[PI3K]] (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions
((Li L, Ren AA, Gao S, Su YS, Yang J, Bockman J, Mericko-Ishizuka P, Griffin J, Shenkar R, Alcazar R, Moore T, Lightle R, DeBiasse D, Awad IA, Marchuk DA, Kahn ML, Burkhardt JK. mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice. Stroke. 2023 Sep 25. doi: 10.1161/STROKEAHA.123.044108. Epub ahead of print. PMID: 37746705.)).

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Ren et al. demonstrated that CCM growth requires increased [[PI3K/AKT/mTOR pathway]] and loss of [[CCM protein]] function. They identified [[PIK3CA]] gain of function (GOF) and CCM loss of function (LOF) somatic mutations in the same cells in a majority of human CCMs. Using mouse models, they showed that CCM growth requires both [[PI3K]] GOF and CCM LOF in [[endothelial cell]]s, and that both CCM LOF and increased expression of the transcription factor [[KLF4]], a downstream [[MEKK3]] effector, augment [[mTOR]] signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor [[Rapamycin]] effectively blocks CCM formation in mouse models. They established a three-hit mechanism analogous to [[cancer]] in which aggressive [[vascular malformation]]s arise through the loss of vascular "[[suppressor gene]]s" that constrain vessel growth and gain of a vascular "[[oncogene]]" that stimulates excess vessel growth. These findings suggest that aggressive CCMs may be treated using clinically approved [[mTORC1]] inhibitors
((Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Mueller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert M, Schwaninger M, Körbelin J, Potente M, Awad IA, Marchuk DA, Kahn ML. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature. 2021 Apr 28. doi: 10.1038/s41586-021-03562-8. Epub ahead of print. PMID: 33910229.)).

[[Gene]]s mutated in [[cerebral cavernous malformation]] (CCM) encode [[protein]]s that modulate junction formation between vascular [[endothelial cell]]s. 

Most cerebral [[cavernous malformation]]s are linked to loss-of-function [[mutation]]s in 1 of 3 [[gene]]s, namely [[CCM1]] (originally called [[KRIT1]]), [[CCM2]] ([[MGC4607]]), or [[CCM3]] ([[PDCD10]]).

How disruption of the CCM complex results in disease remains controversial, with numerous [[signalling pathway]]s (including [[Rho]], SMAD and Wnt/β-catenin) and processes such as [[endothelial mesenchymal transition]] (EndMT) proposed to have causal roles. CCM2 binds to [[MEKK3]]
((Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J,
Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML.
Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4
signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub
2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID:
27027284; PubMed Central PMCID: PMC4864035.
)).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the [[pathogenesis]] of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new [[signaling pathway]]s and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets.
((Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous
Malformations: Review of the Genetic and Protein-Protein Interactions Resulting
in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID:
27896269.
)).

The [[Phosphoinositide 3 kinase]] (PI3K)/[[Akt]] pathway is known to play a major role in [[angiogenesis]]. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten ([[PTEN]]), a [[tumor suppressor]], is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating [[vascular endothelial growth factor]] (VEGF) expression. 

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment
((Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk
to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations.
Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi:
10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.)).
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Studies identify gain of [[MEKK3]] signalling and [[KLF2]]/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics
((Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J,
Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML.
Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4
signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub
2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID:
27027284; PubMed Central PMCID: PMC4864035.
)).

CCMs arise from the loss of an adaptor complex that negatively regulates [[MEKK3]]-[[KLF2]]/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. 
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Tang et al. identify endothelial Toll-like receptor 4 ([[TLR4]]) and the gut [[microbiome]] as critical stimulants of [[cerebral cavernous malformation]] formation. Activation of TLR4 by [[Gram negative bacteria]] or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor [[CD14]] are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment
((Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine
HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes 
C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M,
Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and
the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 
10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.
)).
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In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need
((Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H,
Pasqualini R, Arap W. Emerging Pharmacologic Targets in Cerebral Cavernous
Malformation and Potential Strategies to Alter the Natural History of a Difficult
Disease: A Review. JAMA Neurol. 2018 Nov 26. doi: 10.1001/jamaneurol.2018.3634.
[Epub ahead of print] PubMed PMID: 30476961.
)).

===== References =====