  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.
