Cancer drives atherosclerotic plaque vulnerability by inducing pathological angiogenesis
Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF-α induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.
Authors
- Julius C. Heemelaar (ORCID: https://orcid.org/0000-0001-6892-5227)
- Virginia H. Sun (ORCID: https://orcid.org/0000-0003-1387-2994)
- Nadja Sachs (ORCID: https://orcid.org/0000-0001-8031-017X)
- T N Neilan
- Shaunak Adkar (ORCID: https://orcid.org/0000-0002-8893-2413)
- Nicholas J. Leeper (ORCID: https://orcid.org/0000-0002-0905-2806)
- Richard A. Baylis (ORCID: https://orcid.org/0000-0001-7040-7920)
- Kevin T. Nead (ORCID: https://orcid.org/0000-0001-9680-8298)
- Kai-Uwe Jarr (ORCID: https://orcid.org/0000-0003-3376-6478)
- C. Y. Fu
- Justus Wettich
- Hua Gao (ORCID: https://orcid.org/0000-0002-9698-5830)
- Allen M. Haas
- Lingfeng Luo
- Daniela Ramirez
- Fudi Wang
- Mason Gonzalez
- Hanna Winter
- Moritz von Scheidt
Institutions
- Karolinska University Hospital (SE)
- The University of Texas MD Anderson Cancer Center (US)
- Heidelberg University (DE)
- Cardiovascular Institute of the South (US)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Massachusetts General Hospital (US)
- German Centre for Cardiovascular Research (DE)
- Deutsches Herzzentrum München (DE)
- Technical University of Munich (DE)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-20
- DOI
- https://doi.org/10.64898/2026.01.18.700232
- Primary Topic
- Clusterin in disease pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00