title: The host support niche as a control point for tumor dormancy: implications for tumor development and beyond.
abstract: An increasingly appreciated focus of carcinogenesis research is on mechanisms governing tumor growth after the fact of cancer cell creation. Of particular interest are dynamical interactions between tumor and host cell populations that can themselves strongly impact the fate of established cancer lesions. Regardless of tumor type, all cancers face the common problem of having to breach the barrier of angiogenic competency in order to advance from a microscopic lesion to symptomatic disease. If pre-angiogenic tumor cells are held in dormancy due to cell cycle arrest, this will postpone the need to traverse this higher-level barrier. On the other hand, the barrier itself may prove limiting to a tumor at its diffusion-limited size, creating a population-level dormancy characterized by balanced proliferation and cell death. In both cases of dormancy, the "angiogenic switch" has not yet occurred. We here describe and mathematically quantify an underappreciated third dormancy state defined by an angiogenic balance following the angiogenic switch. In this state we term "post-vascular dormancy," a tumor has attained angiogenic competency, but again demonstrates balanced proliferation and cell death because ambient pro- and anti-angiogenic influences are offsetting. Interestingly, autopsies have shown virtually all of us carry latent tumors in pre- or post-vascular states, many of which lie under the threshold of routine clinical detection. We show how, in the post-vascular case, tumor latency can arise from an elaborate mechanism of self-controlled growth, mediated through the tumor-vascular interaction. Underlying this observation is the finding that a tumor produces both angiogenesis stimulators and inhibitors, with the latter having greater influence, both locally and systemically, as the tumor grows-a mechanism we hypothesize is an aberrant co-option of normal organogenic regulation. That a tumor can limit its own growth raises the prospect that chronic therapies aimed at suppressing this tumor-host dynamic may compare favorably to current strategies which often yield favorable short-term responses but fail to deliver long-term tumor suppression.
authors.affiliation: Tufts University School of Medicine, Boston, MA 02135, USA. Philip.Hahnfeldt@tufts.edu
authors.forename: Philip
authors.initials: P
authors.lastname: Hahnfeldt
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D003510:Cyclohexanes / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016015:Logistic Models; D008657:Metabolic Clearance Rate; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000517:prevention & control; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol