Cancer Metastases: Early Dissemination and Late Recurrences

Friberg, Sten; Nyström, Andreas M.

doi:10.4137/cgm.s31244

Cited by 131 publications

(119 citation statements)

References 93 publications

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“…As the major cause of cancer-related deaths, a full understanding of the metastatic process is of significant value. Multiple recent lines of investigation -including the discovery of the PMN [29], early metastatic seeding [21,23,48], and decreased metastasis in response to treatments with NSAIDs [28,36,46] have brought the long-held view of metastasis as the final, unavoidable step in cancer progression into question, and spurred new experimental and theoretical investigations of the process. Two phenomena that are of particular interest are those of metastatic dormancy and blow-up.…”

Section: Discussionmentioning

confidence: 99%

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

Rhodes

Hillen

2019

Preprint

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Metastatic seeding of distant organs can occur in the very early stages of primary tumor development. Once seeded, these micrometastases may enter a dormant phase that can last decades. Curiously, the surgical removal of the primary tumor can stimulate the accelerated growth of distant metastases, a phenomenon known as metastatic blow-up. Although several theories have been proposed to explain metastatic dormancy and blow-up, most mathematical investigations have ignored the important pro-tumor effects of the immune system. In this work, we address that shortcoming by developing an ordinary differential equation model of the immune-mediated theory of metastasis. We include both anti-and pro-tumor immune effects, in addition to the experimentally observed phenomenon of tumor-induced immune cell phenotypic plasticity. Using geometric singular perturbation analysis, we derive a rather simple model that captures the main processes and, at the same time, can be fully analyzed. Literature-derived parameter estimates are obtained, and model robustness is demonstrated through a sensitivity analysis. We determine conditions under which the parameterized model can successfully explain both metastatic dormancy and blow-up. Numerical simulations suggest a novel measure to predict the occurrence of future metastatic blow-up, in addition to new potential avenues for treatment of clinically undetectable micrometastases.Keywords Mathematical oncology · Cancer modeling · Metastasis · Dormancy · Geometric singular perturbation analysis · Ordinary differential equations Immune-Mediated Metastasis 7 The Reduced Immune-Mediated Metastasis ModelCompared to the original model from [47] we make the following simplifying assumptions.

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Section: Discussionmentioning

confidence: 99%

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

Rhodes

Hillen

2019

Preprint

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“…It is not yet clear if FSS resistance represents a new anti-cancer target. Intervening in the steps of metastatic dissemination for therapeutic benefit is regarded as challenging as it may occur before cancer diagnosis 41 .…”

Section: Discussionmentioning

confidence: 99%

Cancer cells resist mechanical destruction in the circulation via RhoA-myosin II axis

Moose

Krog

Zhao

et al. 2019

Preprint

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During metastasis cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level fluid shear stress (FSS) in vitro relative to non-transformed epithelial cells. Herein we identify a mechanism of FSS resistance in cancer cells, and extend these findings to mouse models of circulating tumor cells (CTCs). We show that cancer cells acutely isolated from primary tumors are resistant to FSS.Our findings demonstrate that cancer cells activate the RhoA-myosin II axis in response to FSS, which protects them from FSS-induced plasma membrane damage. Moreover, we show that the myosin II activity is protective to CTCs in mouse models. Collectively our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.

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“…When the cell suffers from unfavorable factors, such as a lack of nutrition, cytotoxicity, and DNA damage, the cell will enter into a dormant phase (G0/G1 phase) to protect itself from unfavorable factors [22,23]. We analyzed whether the cells enter dormancy (G1/G0 phase) after complete degradation of C1orf109 under long-term CPT treatment.…”

Section: C1orf109l-egfp Degrades Cells Through An Ubiquitinated Protementioning

confidence: 99%

C1orf109L promote R-loop accumulation induced DNA damage to inhibit cell growth

Dou

Xie

et al. 2019

Preprint

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As a function unknown gene, C1orf109 is lower expression in various cells. Here, we reported that C1orf109L, the longest variant of C1orf109, which interacted with R-loop-regulating proteins to trigger R-loop, a three-stranded nucleic acid structure frequently mediated genome instability, accumulation. C1orf109L induce chronic DNA damage to promote P21 upregulation and strongly inhibits cell growth in vitro and in vivo by arresting the cell cycle in the G2 phase. With camptothecin (CPT), an R-loop activator, treatment, C1orf109L further triggers R-loop accumulation-induced DNA damage and promotes cell death by activating cell-death pathway. Furthermore, CPT treatment increases C1orf109L ubiquitination and turnover, which inhibits cell death and promotes the G0/G1 phase of the cell cycle. Therefore, our data illustrated the mechanisms underlying C1orf109L-related cell growth inhibition and provide feasibility and limitations for C1orf109L as a potential target for cancer therapy. Cell proliferation depends on the cell cycle. In abnormal cells, such as benign tumor cells and cancer cells, cell-cycle dis-regulation promotes cell growth [1]. For the cancer therapy strategies are mainly to kill cancer cell or inhibit cancer cell growth. Inducing cancer cell DNA damage is an efficient way to induce cancer cell death or growth inhibition. When genomic DNA is damaged, many pathways involved in cell-cycle regulation are activated, the most important of which involves activation of the DNA-damage checkpoint to arrest the cell cycle at different stages, including G1, S, and G2/M, which ensures that the damaged cell has enough time to repair DNA damage [2,3]. If DNA damage is so severe or the rate of damage is faster than the rate of the repairing process, then the cellular-death pathway is activated [4]. Among the DNA-damage checkpoints, the G1 and G2/M checkpoint restricts mitosis onset in response to multiple exogenous and endogenous factors [5]. With respect to endogenous factors, several proteins act as RNA-processing regulators that control the cell's fate, while dysfunction of RNA-processing-related proteins could trigger R-loop accumulation, and RNA-DNA hybrids can lead to DNA damage and induce-cell cycle arrest, which is an important factor for genome instability in abnormal cells, especially in cancer cells [6,7]. The R-loop also controls gene expression [8] and immunoglobulin (Ig)G class switching [9]. However, the regulation of R-loop proteins is poorly explored. Thus, in this study, we identified the novel gene, c1orf109, which is downregulated in a variety of cell lines. C1orf109L-eGFP expression triggers R-loop accumulation to induce DNA damage and arrest the cell cycle. We report that C1orf109L interacted with R-loop associated proteins and located on R-loops. C1orf109L overexpression that triggered R-loop accumulation no matter with or without CPT treatment in cells. The accumulated R-loops induced DNA damage which inhibits cell growth in vitro and in vivo. In terms of the mechanism underlying cell growth, t...

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Cancer Metastases: Early Dissemination and Late Recurrences

Cited by 131 publications

References 93 publications

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment

Cancer cells resist mechanical destruction in the circulation via RhoA-myosin II axis

C1orf109L promote R-loop accumulation induced DNA damage to inhibit cell growth

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