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Clinical potential of angiogenic therapy and cellular reprogramming

ABSTRACT: Feature Editor Note— You’re driving along the freeway during rush hour. You’re running late and find yourself in bumper-to-bumper traffic. You have 3 options: (1) do nothing, suffer with anguish inside; (2) find productive ways to pass the time, like listen to a podcast or talk on the phone; or (3) get off on the next exit and find an alternative, roundabout path to your destination. Similarly, patients suffering from coronary artery disease can opt to do nothing; stop progression and treat their symptoms with medical therapy; or undergo revascularization either percutaneously or surgically. There are few options, however, for those who develop chronic coronary artery disease without suitable revascularization strategies. They have missed their exit and are stuck in this metaphorical traffic jam, with no radio and no cell phone. These patients may experience refractory angina or develop ischemic cardiomyopathy and heart failure. Exploring solutions to this increasingly widespread problem is imperative. Chronic heart failure is rising, while the number of organs available for transplantation remains limited. Similarly, bridge therapies such as ventricular assist devices are resource intensive and are typically only performed at select, high-volume institutions. In the following article, the authors explore cardiac regenerative strategies to bridge this therapeutic gap. They delve into a so-called “biologic bypass,” which aims to restore perfusion and functionality of ischemic myocardium. Specifically, they review published preclinical data and the potential clinical implementation of cardiac reprogramming of fibrotic tissue into functioning, contractile myocardium, as well as angiogenic therapies aimed at inducing angiogenesis. These innovative and forward-thinking approaches will be necessary to combat the challenges faced by the heart specialists of tomorrow.w Jordan Dozier, MD, and Nahush A. Mokadam, MD

SUBMITTER: Ryan C

PROVIDER: S-EPMC8570572 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY:Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION:A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies.

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Clinical potential of angiogenic therapy and cellular reprogramming

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