Background

The role of connective tissue growth factor (CTGF/CCN2) in pathological angiogenesis in the retina is unknown.

Results

CTGF/CCN2 stimulates retinal neovascularization through transactivation of p53 target genes such as matrix metalloproteinase (MMP)-2.

Conclusion

CTGF/CCN2 effects on abnormal vessel formation in the retina are mediated by p53 and MMP-2.

Significance

CTGF/CCN2 and its downstream effectors are potential targets in the development of new antiangiogenic treatments. Pathological angiogenesis in the retina is driven by dysregulation of hypoxia-driven stimuli that coordinate physiological vessel growth. How the various components of the neovascularization signaling network are integrated to yield pathological changes has not been defined. Connective tissue growth factor (CTGF/CCN2) is an inducible matricellular protein that plays a major role in fibroproliferative disorders. Here, we show that CTGF/CCN2 was dynamically expressed in the developing murine retinal vasculature and was abnormally increased and localized within neovascular tufts in the mouse eye with oxygen-induced retinopathy. Consistent with its propitious vascular localization, ectopic expression of the CTGF/CCN2 gene further accelerated neovascularization, whereas lentivirus-mediated loss-of-function or -expression of CTGF/CCN2 harnessed ischemia-induced neovessel outgrowth in oxygen-induced retinopathy mice. The neovascular effects of CTGF/CCN2 were mediated, at least in part, through increased expression and activity of matrix metalloproteinase (MMP)-2, which drives vascular remodeling through degradation of matrix and non matrix proteins, migration and invasion of endothelial cells, and formation of new vascular patterns. In cultured cells, CTGF/CCN2 activated the MMP-2 promoter through increased expression and tethering of the p53 transcription factor to a highly conserved p53-binding sequence within the MMP-2 promoter. Concordantly, the neovascular effects of CTGF/CCN2 were suppressed by p53 inhibition that culminated in reduced enrichment of the MMP-2 promoter with p53 and decreased MMP-2 gene expression. Our data identified new gene targets and downstream effectors of CTGF/CCN2 and provided the rational basis for targeting the p53 pathway to curtail the effects of CTGF/CCN2 on neovessel formation associated with ischemic retinopathy.

Background

Recruitment of a diverse participant pool to cancer clinical trials is an essential component of clinical research as it improves the generalizability of findings. Investigating and piloting novel recruitment strategies that take advantage of ubiquitous digital technologies has become an important component of facilitating broad recruitment and addressing inequities in clinical trial participation. Equitable and inclusive recruitment improves generalizability of clinical trial outcomes, benefiting patients, clinicians, and the research community. The increasing prevalence of online connectivity in the USA and use of the Internet as a resource for medical information provides an opportunity for digital recruitment strategies in cancer clinical trials. This study aims to measure the acceptability, preliminary estimates of efficacy, and feasibility of the Trial Library intervention, an Internet-based cancer clinical trial matching tool. This study will also examine the extent to which the Trial Library website, designed to address the linguistic and literacy needs of broader patient populations, influences patient-initiated conversations with physicians about clinical trial participation.

Methods

This is a study protocol for a non-randomized, single-arm pilot study. This is a mixed methods study design that utilizes the statistical analysis of quantitative survey data and the qualitative analysis of interview data to assess the participant experience with the Trial Library intervention. This study will examine (1) acceptability as a measure of participant satisfaction with this intervention, (2) preliminary measure of efficacy as a measure of proportion of participants with documented clinical trial discussion in the electronic medical record, and (3) feasibility of the intervention as a measure of duration of clinical visit.

Discussion

The principles that informed the design of the Trial Library intervention aim to be generalizable to clinical trials across many disease contexts. From the ground up, this intervention is built to be inclusive of the linguistic, literacy, and technological needs of underrepresented patient populations. This study will collect essential preliminary data prior to a multi-site randomized clinical trial of the Trial Library intervention.

Trial registration

This study has received institutional approval from the Committee of Human Subjects Research at the University of California, San Francisco.