Abstract
Objective:we present a multiscale agent-based model of Ductal Carcinoma in Situ (DCIS) in order to gain a detailed understanding of the cell-scale population dynamics, phenotypic distributions, and the associated interplay of important molecular signaling pathways that are involved in DCIS ductal invasion into the duct cavity (a process we refer to as duct advance rate here).Methods:DCIS is modeled mathematically through a hybridized discrete cell-scale model and a continuum molecular scale model, which are explicitly linked through a bidirectional feedback mechanism.Results:we find that duct advance rates occur in two distinct phases, characterized by an early exponential population expansion, followed by a long-term steady linear phase of population expansion, a result that is consistent with other modeling work. We further found that the rates were influenced most strongly by endocrine and paracrine signaling intensity, as well as by the effects of cell density induced quiescence within the DCIS population.Conclusion:our model analysis identified a complex interplay between phenotypic diversity that may provide a tumor adaptation mechanism to overcome proliferation limiting conditions, allowing for dynamic shifts in phenotypic populations in response to variation in molecular signaling intensity. Further, sensitivity analysis determined DCIS axial advance rates and calcification rates were most sensitive to cell cycle time variation.Significance:this model may serve as a useful tool to study the cell-scale dynamics involved in DCIS initiation and intraductal invasion, and may provide insights into promising areas of future experimental research.
Highlights
B REAST cancer is the most frequently diagnosed form of cancer in the United States, with 239,109 new cases diagnosed in 2014 alone [1]
In our agent-based modeling (ABM), cells are represented as unique, discrete entities, while molecular signaling profiles and molecular movement are represented as continuums through a mathematical description using partial differential equations (PDEs) which are solved numerically at each time step
In a study measuring 1,285 excised human mammary ducts, Mayr et al reported a mean diameter of 90 μm for the normal duct (520 samples, range 39−314 μm), but a statistically significant increased mean diameter of 314 μm (765 samples, range 60−1708 μm) in ducts with intraductal carcinoma [71]
Summary
B REAST cancer is the most frequently diagnosed form of cancer in the United States, with 239,109 new cases diagnosed in 2014 alone (the most recent year complete statistics reported; 236,968 cases in women and 2,141 in men) [1]. This translates to roughly 12% of women experiencing a positive diagnosis within their lifetime. Carcinomas in situ constitute roughly 20% of all cancers of the breast [2], [3], with the majority (∼83%) occurring within the mammary gland duct, known as ductal carcinoma in situ (DCIS) [4]. The debate over if and when to treat DCIS continues, as even the most aggressive estimates of DCIS transitioning to invasive cancer suggest it occurs in only 1 in 3 cases [6], highlighting the need for tools to prevent overdetection and overtreatment
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