Vasculopathy as a mechanical barrier to cancer spread: Clinical evidence and a rheology-based model in lung cancer and other solid tumors

Metastatic dissemination in lung cancer (LC) and other solid tumors is influenced not only by tumor-intrinsic biology and immune–inflammatory responses, but also by the physical properties of the vascular system through which circulating tumor cells (CTCs) migrate. Peripheral arterial disease (PAD), particularly when associated with aneurysmal dilation, is frequent among long-term smokers and is characterized by chronic vascular inflammation and altered hemodynamics. We hypothesized that PAD-related vascular remodeling and rheological alterations may influence tumor metastatic capacity. Through a retrospective analysis of 976 patients diagnosed with both cancer and arteriopathy between 2018 and 2024, a cohort of 120 individuals with concomitant aneurysmal and neoplastic disease was identified, with non-small cell lung cancer (NSCLC) considered the primary biologically interpretable model. Metastatic burden at diagnosis was compared with that of an unselected LC population from the same institution and with literature-reported data. Within this framework, a phenomenological biophysical model was developed linking inflammation-driven changes in blood viscosity to metastatic competence, and a Monte Carlo approach was used to estimate metastasis probability under control and PAD-like conditions. Despite marked male predominance and high smoking exposure, the study cohort exhibited an unexpectedly low metastatic burden, with 13.3% of patients presenting metastatic disease at diagnosis and only 7.6% showing extrathoracic dissemination, compared with an expected rate of approximately 30%. Multivariable analysis and partition modeling identified arteriopathy as the dominant factor associated with reduced metastatic dissemination, whereas conventional tumor and inflammatory biomarkers showed limited explanatory value. The rheological model indicated that once inflammation exceeds a critical threshold, increased blood viscosity and disturbed flow patterns may act as a mechanical filter impairing CTC extravasation. Monte Carlo simulations supported this threshold-dependent mechanism, showing an approximately 50% reduction in predicted metastatic rates in PAD-like conditions compared with controls. Collectively, these findings suggest that chronic PAD and aneurysmal vasculopathy may reshape the circulatory microenvironment, with NSCLC providing a mechanistically interpretable framework for a transition from a metastasis-permissive to a metastasis-restrictive rheological regime.