Global Dormancy of Metastases Due to Systemic Inhibition of Angiogenesis

TL;DR

This paper presents a mathematical model explaining how systemic angiogenesis inhibition can lead to global dormancy of metastases, potentially informing new therapeutic strategies for metastatic cancer.

Contribution

It introduces a novel organism-scale model that accounts for systemic angiogenesis inhibition affecting all tumor lesions, explaining metastasis dormancy observed in autopsies.

Findings

Systemic angiogenesis inhibition can suppress all metastases.

The model identifies parameter ranges leading to tumor dormancy.

Global tumor burden can reach a steady state due to mutual inhibition.

Abstract

Autopsy studies of adults dying of non-cancer causes have shown that virtually all of us possess occult, cancerous lesions. This suggests that, for most individuals, cancer will become dormant and not progress, while only in some will it become symptomatic disease. Meanwhile, it was recently shown in animal models that a tumor can produce both stimulators and inhibitors of its own blood supply. To explain the autopsy findings in light of the preclinical research data, we propose a mathematical model of cancer development at the organism scale describing a growing population of metastases, which, together with the primary tumor, can exert a progressively greater level of systemic angiogenesis-inhibitory influence that eventually overcomes local angiogenesis stimulation to suppress the growth of all lesions. As a departure from modeling efforts to date, we look not just at signaling from and effects on the primary tumor, but integrate over this increasingly negative global signaling from all sources to track the development of total tumor burden. This in silico study of the dynamics of the tumor/metastasis system identifies ranges of parameter values where mutual angio-inhibitory interactions within a population of tumor lesions could yield global dormancy, i.e., an organism-level homeostatic steady state in total tumor burden. Given that mortality arises most often from metastatic disease rather than growth of the primary per se, this finding may have important therapeutic implications.