Drug-Induced Resistance in Micrometastases: Analysis of Spatio-Temporal Cell Lineages

Pérez-Velázquez, Judith; Rejniak, Katarzyna A.

doi:10.3389/fphys.2020.00319

Cited by 24 publications

(26 citation statements)

References 52 publications

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“…Moreover, tumor cells promote angiogenesis directly and indirectly by increasing the proangiogenic activity of TAMs [14]. Finally, the tumor microenvironment (TME) protects cancer cells from drug activity and reduces drug penetration by forming "sanctuaries" [15].…”

Section: Introductionmentioning

confidence: 99%

The CCL5/CCR5 Axis in Cancer Progression

Aldinucci

Borghese

Casagrande

2020

Cancers

263

191

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Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.

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Section: Introductionmentioning

confidence: 99%

The CCL5/CCR5 Axis in Cancer Progression

Aldinucci

Borghese

Casagrande

2020

Cancers

263

191

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“…t) 0), and their respective maturation ages C mat i1 and C mat i2 are inherited from the mother cell maturation age with a small noise term ϵ mat to avoid cell cycle synchronisation between the cells [17,26]:…”

Section: Cell Growth and Divisionmentioning

confidence: 99%

Collective Cell Migration in a Fibrous Environment: A Hybrid Multiscale Modelling Approach

Suveges

Chamseddine²,

Rejniak³

et al. 2021

Front. Appl. Math. Stat.

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The specific structure of the extracellular matrix (ECM), and in particular the density and orientation of collagen fibres, plays an important role in the evolution of solid cancers. While many experimental studies discussed the role of ECM in individual and collective cell migration, there are still unanswered questions about the impact of nonlocal cell sensing of other cells on the overall shape of tumour aggregation and its migration type. There are also unanswered questions about the migration and spread of tumour that arises at the boundary between different tissues with different collagen fibre orientations. To address these questions, in this study we develop a hybrid multi-scale model that considers the cells as individual entities and ECM as a continuous field. The numerical simulations obtained through this model match experimental observations, confirming that tumour aggregations are not moving if the ECM fibres are distributed randomly, and they only move when the ECM fibres are highly aligned. Moreover, the stationary tumour aggregations can have circular shapes or irregular shapes (with finger-like protrusions), while the moving tumour aggregations have elongate shapes (resembling to clusters, strands or files). We also show that the cell sensing radius impacts tumour shape only when there is a low ratio of fibre to non-fibre ECM components. Finally, we investigate the impact of different ECM fibre orientations corresponding to different tissues, on the overall tumour invasion of these neighbouring tissues.

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“…In cancer, chemotherapeutic drugs perfuse more thoroughly through regions near the vasculature (source habitat) than habitats farther from vasculature (sink habitat). The diffusion dynamics that reduce nutrient concentrations away form blood vessels also reduces the concentration of systemically delivered drugs (Perez-Velazquez and Rejniak, 2020).…”

Section: Modeling Treatmentmentioning

confidence: 99%

Coupled Source-Sink Habitats Produce Spatial and Temporal Variation of Cancer Cell Molecular Properties as an Alternative to Branched Clonal Evolution and Stem Cell Paradigms

et al. 2021

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Intratumoral molecular cancer cell heterogeneity is conventionally ascribed to the accumulation of random mutations that occasionally generate fitter phenotypes. This model is built upon the “mutation-selection” paradigm in which mutations drive ever-fitter cancer cells independent of environmental circumstances. An alternative model posits spatio-temporal variation (e.g., blood flow heterogeneity) drives speciation by selecting for cancer cells adapted to each different environment. Here, spatial genetic variation is the consequence rather than the cause of intratumoral evolution. In nature, spatially heterogenous environments are frequently coupled through migration. Drawing from ecological models, we investigate adjacent well-perfused and poorly-perfused tumor regions as “source” and “sink” habitats, respectively. The source habitat has a high carrying capacity resulting in more emigration than immigration. Sink habitats may support a small (“soft-sink”) or no (“hard-sink”) local population. Ecologically, sink habitats can reduce the population size of the source habitat so that, for example, the density of cancer cells directly around blood vessels may be lower than expected. Evolutionarily, sink habitats can exert a selective pressure favoring traits different from those in the source habitat so that, for example, cancer cells adjacent to blood vessels may be suboptimally adapted for that habitat. Soft sinks favor a generalist cancer cell type that moves between the environment but can, under some circumstances, produce speciation events forming source and sink habitat specialists resulting in significant molecular variation in cancer cells separated by small distances. Finally, sink habitats, with limited blood supply, may receive reduced concentrations of systemic drug treatments; and local hypoxia and acidosis may further decrease drug efficacy allowing cells to survive treatment and evolve resistance. In such cases, the sink transforms into the source habitat for resistant cancer cells, leading to treatment failure and tumor progression. We note these dynamics will result in spatial variations in molecular properties as an alternative to the conventional branched evolution model and will result in cellular migration as well as variation in cancer cell phenotype and proliferation currently described by the stem cell paradigm.

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Drug-Induced Resistance in Micrometastases: Analysis of Spatio-Temporal Cell Lineages

Cited by 24 publications

References 52 publications

The CCL5/CCR5 Axis in Cancer Progression

The CCL5/CCR5 Axis in Cancer Progression

Collective Cell Migration in a Fibrous Environment: A Hybrid Multiscale Modelling Approach

Coupled Source-Sink Habitats Produce Spatial and Temporal Variation of Cancer Cell Molecular Properties as an Alternative to Branched Clonal Evolution and Stem Cell Paradigms

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