A Mathematical-Biological Joint Effort to Investigate the Tumor-Initiating Ability of Cancer Stem Cells

Abstract

The involvement of Cancer Stem Cells (CSCs) in tumor progression and tumor recurrence is one of the most studied subjects in current cancer research. The CSC hypothesis states that cancer cell populations are characterized by a hierarchical structure that affects cancer progression. Due to the complex dynamics involving CSCs and the other cancer cell subpopulations, a robust theory explaining their action has not been established yet. Some indications can be obtained by combining mathematical modeling and experimental data to understand tumor dynamics and to generate new experimental hypotheses. Here, we present a model describing the initial phase of ErbB2+ mammary cancer progression, which arises from a joint effort combing mathematical modeling and cancer biology. The proposed model represents a new approach to investigate the CSC-driven tumorigenesis and to analyze the relations among crucial events involving cancer cell subpopulations. Using in vivo and in vitro data we tuned the model to reproduce the initial dynamics of cancer growth, and we used its solution to characterize observed cancer progression with respect to mutual CSC and progenitor cell variation. The model was also used to investigate which association occurs among cell phenotypes when specific cell markers are considered. Finally, we found various correlations among model parameters which cannot be directly inferred from the available biological data and these dependencies were used to characterize the dynamics of cancer subpopulations during the initial phase of ErbB2+ mammary cancer progression.

Operating principles of Notch–Delta–Jagged module of cell–cell communication

“…Future modeling studies should explore the interplay between Notch, inflammation and asymmetric versus symmetric cell division of CSCs in a cell-population model. Many models have explored the effect of CSCs on tumor progression in terms of population dynamics, but without considering any cell-cell communication [96][97][98][99]. Since cell-cell communication is fundamental during collective decision-making of many populations, an understanding of tumor progression without considering cell-cell interaction via NDJ signaling is incomplete, and hence cannot be utilized to plan an effective and strategic 'cyber war' against them [100].…”

NK cells control breast cancer and related cancer stem cell hematological spread

“…4 Cancer stem cells (CSCs) have recently been proposed as a key compartment of the tumor population. 5,6 Similarly to normal stem cells, CSCs are a slowly proliferating population which is able to self-renew and give rise to more differentiated cells that compose the bulk of a tumor. 7 CSCs have also been hypothesized to be a crucial factor in tumor recurrence, due to their intrinsic resistance to drugs and irradiation which often enables them to survive traditional therapies.…”

A versatile mathematical work-flow to explore how Cancer Stem Cell fate influences tumor progression

“…After this preliminary validation, our methodology has been applied to a CSC-tumor model which extends a previous representation of the same phenomenon that we have published in [18] and that aims to figure out which are the phenotypic parameters that drive cancer growth.…”