Migration rules: tumours are conglomerates of self-metastases

Enderling, Heiko; Hlatky, Lynn; Hahnfeldt, Philip

doi:10.1038/sj.bjc.6605071

Cited by 119 publications

(167 citation statements)

References 36 publications

(49 reference statements)

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“…S1). These results are paralleled by recent findings in a different model system in which high migration levels in a small subset of cells give rise to small proliferating extratumoral lesions and therefore tumors are "conglomerates of self-metastasis" as the authors propose (24).…”

Section: Resultssupporting

confidence: 74%

Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity

et al. 2010

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The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46-56. ©2010 AACR.

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Section: Resultssupporting

confidence: 74%

Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity

et al. 2010

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“…2B). The pattern of the resulting tumor growth can be described as a conglomeration of individual tumors, an idea that has been proposed previously (47,48). In contrast, tumors forming from stem cells with more potent progeny (ρ = 15, 20) could not initiate significant growth, as the stem cells were less often exposed to space and hence divided less often, either asymmetrically or symmetrically.…”

Section: Resultsmentioning

confidence: 94%

“…In none of the simulations of tumors arising from progeny with proliferation capacity of ρ = 20 was symmetrical division seen within the first t = 365 days. At later times, with ρ = 15 and ρ = 20 the tumors form conglomerates of individual tumors as well, with overall tumor cell numbers inversely depending on progeny proliferation capacity ρ max (48).…”

Section: Resultsmentioning

confidence: 99%

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

et al. 2009

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Even after a tumor is established, it can early on enter a state of dormancy marked by balanced cell proliferation and cell death. Disturbances to this equilibrium may affect cancer risk, as they may cause the eventual lifetime clinical presentation of a tumor that might otherwise have remained asymptomatic. Previously, we showed that cell death, proliferation, and migration can play a role in shifting this dynamic, making the understanding of their combined influence on tumor development essential. We developed an individual cell-based computer model of the interaction of cancer stem cells and their nonstem progeny to study early tumor dynamics. Simulations of tumor growth show that three basic components of tumor growth-cell proliferation, migration, and death-combine in unexpected ways to control tumor progression and, thus, clinical cancer risk. We show that increased proliferation capacity in nonstem tumor cells and limited cell migration overall lead to space constraints that inhibit proliferation and tumor growth. By contrast, increasing the rate of cell death produces the expected tumor size reduction in the short term, but results ultimately in paradoxical accelerated long-term growth owing to the liberation of cancer stem cells and formation of self-metastases.

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“…Based on the analysis of their phenotype and similarly to other investigators, 43,55 we hypothesize that at some point (possibly shortly after the The table summarizes similarities and differences between the metastasis neuroblastoma (MetNB) and the disseminated neuroblastoma (DisNB) variants.…”

Section: Discussionmentioning

confidence: 99%

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Botzer

Maman

Sagi‐Assif

et al. 2011

The American Journal of Pathology

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The mechanism by which dormant tumor cells can begin growing after long periods of inactivity and accelerate disease recurrence is poorly understood. The present study characterizes dormant neuroblastoma (NB) cells, as well as metastatic cells, which reside in the same organ microenvironment. A xenograft model of human NB consisting of variants that generate nonmetastatic local tumors in the orthotopic inoculation site and variants that generate lung metastatic NB (MetNB) cells was developed in our laboratory. The present study shows that lungs of mice inoculated with nonmetastatic NB variants contain disseminated neuroblastoma (DisNB) human cells. Both DisNB and MetNB variants expressed a similar tumorigenicty phenotype in vivo, whereas the MetNB variants produced a heavy metastatic load and the DisNB variants produced no or little metastasis. A comparative in vitro characterization of MetNB and DisNB cells revealed similarities and differences. DisNB, but not MetNB cells, expressed the minimal residual disease markers PHOX2B and TH. MetNB cells demonstrated higher migratory capacity, an elevated matrix metalloproteinase (MMP) secretion, and a higher constitutive phosphorylation of extracellular signalregulated kinase (ERK) than DisNB cells. We suggest that characteristics common to both MetNB and DisNB cells were acquired relatively early in the metastatic process and the characteristics that differ between these variants were acquired later. We hypothesize that the DisNB cells are metastasis precursors, which may progress toward metastasis under certain microenvironmental conditions. Neuroblastoma (NB) is the most common extracranial solid tumor in children comprising 8% to 10% of all childhood cancers. More than half of these patients have a metastatic disease at diagnosis. 1-3 NB cells disseminate either by hematogenous spread, producing metastasis most frequently in bone marrow, bone, liver, and skin, or by lymphatic spread to regional and distant lymph nodes. 4 Lung metastases are considered a terminal event representing a widely disseminated metastatic disease. [5][6] Approximately 50% of children with high-risk NB that complete consolidation therapy develop early or late relapse, often from minimal residual disease in the form of circulating NB cells or micrometastases. 7 Most of the children with NB present metastatic disease at diagnosis with poor outcome, despite intensive treatment protocols. 8 The presence of circulating NB cells and/or NB micrometastasis may indicate a significant high-risk disease. 9 However, the question whether NB micrometastases develop into metastatic disease is yet to be answered.Previous studies from our laboratory were aimed to identify molecular pathways that are involved in NB metastasis. We focus on the cross talk between metastatic NB cells and components of their microenvironment, and on the downstream effects of such interactions.We suggested that NB cells might use chemokinechemokine receptor axes in their progression to metastasis. For example the CXCR4 -CXCL12 10 ...

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Migration rules: tumours are conglomerates of self-metastases

Cited by 119 publications

References 36 publications

Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity

Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

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