The overshoot and phenotypic equilibrium in characterizing cancer dynamics of reversible phenotypic plasticity

Xiufang Chen, Yue Wang, Tianquan Feng, Ming Yi, Xingan Zhang, Da Zhou

(Submitted on 16 Mar 2015)

The paradigm of phenotypic plasticity indicates reversible relations of different cancer cell phenotypes, which challenges the cellular hierarchy proposed by the conventional cancer stem cell (CSC) theory. Since the validity of the reversible model versus the hierarchical model of cancer cells is still experimentally debated, it is worthwhile to theoretically explore the dynamic behavior characterizing the reversible model in comparison of the hierarchical model. By comparing the two models in predicting the cell-state dynamics observed in biological experiments, our results imply that the reversible model has advantages over the hierarchical model in predicting both long-term stable and short-term transient dynamics of cancer cells. In particular, it is found that i) the reversible model can predict the phenotypic equilibrium better than the hierarchical model, namely, the stability of the phenotypic mixture of cancer cells is more rooted in the reversible model; ii) the reversible model can perform various types of overshoot behavior, whereas the hierarchical model can never predict the overshoot of CSCs proportion. These also indicate that the phenotypic equilibrium and overshoot can be good candidates to characterize the models with the reversible phenotypic plasticity.

http://arxiv.org/abs/1503.04558

The Cancer Diaspora: Metastasis beyond the seed and soil hypothesis

Kenneth J. Pienta, Bruce Robertson, Donald S. Coffey, Russell S. Taichman

(Submitted on 8 Aug 2013)

Do cancer cells escape their confinement of their original habitat in the primary tumor or are they forced out by ecological changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, diaspora has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For example, ecological traps, habitats that lead to the extinction of a species, can be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy.

http://arxiv.org/abs/1308.1938

Maximum Tolerated Dose Versus Metronomic Scheduling in the Treatment of Metastatic Cancers

This paper was posted to the arxiv along with another paper, titled

Quantitative Analysis of the Tumor/Metastasis 

System and its Optimal Therapeutic Control

The authors are clearly interested in the implications of optimal control in the metastatic setting. The paper below leaves me wondering from an evolutionary selection point of view, if metronomic therapy is actually increasing the probability of metastasis.

Maximum Tolerated Dose Versus Metronomic Scheduling in the Treatment of Metastatic Cancers

Authors

Sébastien Benzekry, Philip Hahnfeldt

Abstract

Although optimal control theory has been used for the theoretical study of anticancerous drugs scheduling optimization,with the aim of reducing the primary tumor volume, the effect on metastases is often ignored. Here, we use a previously published model for metastatic development to define an optimal control problem at the scale of the entire organism of the patient. In silico study of the impact of different scheduling strategies for anti-angiogenic and cytotoxic agents (either in monotherapy or in combination) is performed to compare a low-dose, continuous, metronomic administration scheme with a more classical maximum tolerated dose schedule. Simulation results reveal differences between primary tumor reduction and control of metastases but overall suggest use of the metronomic protocol.

Link to the arxiv