Impact of host ageing on the metastatic phenotype

Meehan, Brian; Dombrovsky, Alexander; Lau, Karrie; Lai, Tiffany; Magnus, Nathalie; Montermini, Laura; Rak, Janusz

doi:10.1016/j.mad.2013.02.001

Cited by 8 publications

(12 citation statements)

References 50 publications

(92 reference statements)

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“…Indeed, vasculature is central to bidirectional trafficking of bone marrow-derived, inflammatory cells and metastatic cells in and out of the tumor mass, respectively ( Fidler2003; Folkman2007; Mantovani and Locati 2013), and these processes may change with organismal agenig. In support of this notion, we and others have documented age-related alterations in tumor angiogenesis (Pili et al 1994;Franco et al 2002;Reed and Edelberg 2004;Shimada et al 2004;Klement et al 2007) and metastasis (Ershler et al 1983;Meehan et al 2013), in both experimental and clinical settings (Meehan et al 2011).…”

Section: Introductionsupporting

confidence: 65%

“…Indeed, the existence of time-dependent, but individually variable and complex contributions of biological processes associated with ageing may be important to take into account in the context of precision (individualized) cancer care, which is currently dominated by genetic considerations. We postulate that atherosclerosis and other manifestations of the vascular ageing could impact cancer progression and therapy in multiple ways, even through selection of aggressive cellular populations (Meehan, Dombrovsky, Lau, Lai, Magnus, Montermini, and Rak 2013;Magnus et al 2014). It should also be noted that vascular ageing, comorbidities and cancer may also be affected by gender and other factors that were not tested in the present manuscript, but deserve future attention.…”

Section: Discussionmentioning

confidence: 83%

“…For example, we observed that tumor tissues in the case of older ccRCC patients exhibit higher MVD scores and changes in expression of important molecular markers such as nitric oxide synthase (eNOS), in spite of comparable tumor sizes between both groups (Meehan, Appu, St, Rak-Poznanska, Klotz, and Rak 2011). Similarly, we have documented that age may change the nature, but not necessarily the magnitude of experimental metastasis (Meehan, Dombrovsky, Lau, Lai, Magnus, Montermini, and Rak 2013). Finally, in the present study, multiple and dramatic qualitative changes in the tumor interior accompany a somewhat greater clinical response of experimental LCC to sunitinib therapy.…”

Section: Discussionmentioning

confidence: 87%

“…Our previous study documented that the same types of cancer cells, including LLC, exhibit different growth and metastatic capacities, and different responses to metronomic chemotherapy when transplanted to aged and atherosclerotic mice, compared to their young counterparts used routinely in these kinds of studies (Klement, St Croix, Milsom, May, Guo, Yu, Klement, and Rak 2007;Meehan, Dombrovsky, Lau, Lai, Magnus, Montermini, and Rak 2013). This prompted us to examine whether an approved, clinically relevant and molecularly targeted antiangiogenic agent, such as sunitinib malate, would exhibit similar or differential activity against well characterized tumors in young versus aged mice.…”

Section: Age-related Responses Of Tumors To Sunitinibmentioning

confidence: 99%

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Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Meehan

Garnier

Dombrovsky

et al. 2014

Mechanisms of Ageing and Development

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Abbreviations: LLC -Lewis lung carcinoma; MVD -microvascular density; CAIX -carbonyl anhydrase IX 2 AbstractAntiangiogenic therapies in cancer exert their effects in the context of age-related comorbidities, which affect the entirety of the vascular system. Among those conditions, the impact of atherosclerosis is especially prevalent, but poorly understood, and not reflected in mouse models routinely used for testing antiangiogenic therapeutics. Our earlier work suggested that these obstacles can be overcome with the use of atherosclerosis-prone ApoE-/-mice harbouring syngeneic transplantable Lewis Lung Carcinoma (LLC). Here we report that, sunitinib, the clinically approved, antiangiogenic inhibitor impedes global tumor growth to a greater extent in aged then in young mice. This activity was coupled with changes in the tumor microenvironment, which in aged mice was characterized by pronounced hypoxia, reduction in microvascular density (MVD) and lower pericyte coverage, relative to young controls. We also detected soluble VEGR2 in plasma of sunitinib treated mice. Interestingly, sunitinib modulated tumor infiltration with bone marrow-derived cells (CD45+), recruitment of M2-like macrophages (CD163+) and activation of inflammatory pathways (phospho-STAT3) in a manner that was agedependent. We suggest that age and atherosclerosis may alter the effects of sunitinib on the tumor microenvironment, and that these considerations may also apply more broadly to other forms of antiangiogenic treatment in cancer.

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 87%

Section: Age-related Responses Of Tumors To Sunitinibmentioning

confidence: 99%

See 2 more Smart Citations

Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Meehan

Garnier

Dombrovsky

et al. 2014

Mechanisms of Ageing and Development

Self Cite

View full text Add to dashboard Cite

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“…The development of malignancies due to the uncontrolled influence of some enrichment in “youth stimuli” in an aged systemic environment have been previously suggested. 29 Such stimuli seem to exist: Conboy et al 1 reported an increase in the stem cell proliferation from old donors when the cells were cultured in media containing serum from younger animals; however, such stimuli may have some undesired effects for the whole body in vivo . On the other hand, we observed the opposite effect when assessing the occurrence of ovarian cysts—their frequency tended to be lower in plasma-treated mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aged Mice Repeatedly Injected with Plasma from Young Mice: A Survival Study

Shytikov

Balva

Debonneuil³

et al. 2014

BioResearch Open Access

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It was reported using various biological models that the administration of blood factors from young animals to old animals could rejuvenate certain functions. To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10–12 months was treated by repeated injections of plasma from 2- to 4-month-old females (averaging 75–150 μL per injection, once intravenously and once intraperitoneally per week for 16 months). Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.

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Oncogenic RAS drives the CRAF‐dependent extracellular vesicle uptake mechanism coupled with metastasis

Choi

Montermini

Meehan

et al. 2021

J of Extracellular Vesicle

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Oncogenic RAS impacts communication between cancer cells and their microenvironment, but it is unclear how this process influences cellular interactions with extracellular vesicles (EVs). This is important as intercellular EV trafficking plays a key role in cancer invasion and metastasis. Here we report that overexpression of mutant RAS drives the EV internalization switch from endocytosis (in non‐transformed cells) to macropinocytosis (in cancer cells) resulting in enhanced EV uptake. This process depends on the surface proteoglycan, fibronectin and EV engulfment mechanism regulated by CRAF. Both mutant RAS and activated CRAF expression is associated with formation of membrane ruffles to which they colocalize along with actin, sodium‐hydrogen exchangers (NHEs) and phosphorylated myosin phosphatase (pMYPT). RAS‐transformed cells internalize EVs in the vicinity of ruffled structures followed by apparent trafficking to lysosome and degradation. NHE inhibitor (EIPA) suppresses RAS‐driven EV uptake, along with adhesion‐independent clonal growth and experimental metastasis in mice. Thus, EV uptake may represent a targetable step in progression of RAS‐driven cancers.

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Impact of host ageing on the metastatic phenotype

Cited by 8 publications

References 50 publications

Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Aged Mice Repeatedly Injected with Plasma from Young Mice: A Survival Study

Oncogenic RAS drives the CRAF‐dependent extracellular vesicle uptake mechanism coupled with metastasis

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