Brain metastasis is associated with a particular poor prognosis. Novel insight into the brain metastatic process is therefore warranted. Several preclinical models of brain tumor metastasis have been developed during the last 60 years, and they have in part revealed some of the mechanisms underlying the metastatic process. This review discusses mechanisms of brain metastasis with a key focus of the development of animal model systems. This includes the use of rodent, syngeneic brain metastasis models (spontaneous, chemically induced and genetically engineered models) and human xenotransplantation models (ectopic inoculation and orthotopic models). Current information indicates that none of these fully reflect tumor development seen in patients with metastatic disease. The various model systems used, however, have provided important insight into specific mechanisms of the metastatic process related to the brain. By combining the knowledge obtained from animal models, new important information on the molecular mechanisms behind metastasis will be obtained, leading to the future development of new therapeutic strategies.
Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.
In a large patient cohort and in a robust animal model, we show that although LDHA expression varies biphasically during melanoma brain metastasis formation, tumor progression and survival seem to be functionally independent of LDHA.
Koronapandemien har synliggjort nødvendigheten av prioriteringer i helsetjenesten vår. Helseprioriteringer i Norge skal gjøres etter de tre kriteriene nytte, ressurs og alvorlighetsgrad. Nytte-og ressurskriteriene utgjør til sammen et kostnadseffektivitetskriterium: Høyere prioritet tilfaller tiltak som skaper mye helse med få ressurser. Alvorlighetskriteriet innebaerer at en mer alvorlig tilstand kan og skal prioriteres høyere enn kostnadseffektiviteten alene tilsier. I denne artikkelen undersøker vi det norske alvorlighetskriteriet for helseprioriteringer i møte med koronaepidemien i Norge. Vi beskriver utviklingen av alvorlighetskriteriet i den norske prioriteringsdiskursen. Videre diskuterer vi hvordan koronaepidemien fremhever uenigheter og tvetydigheter rundt begrepet «alvorlighet» hva gjelder dødsrisiko, komorbiditet og hastegrad. Vi drøfter også hvordan den norske pandemiberedskapen passer inn i dette landskapet og etterlyser en klarere forståelse av alvorlighet i skillet mellom behandling og forebygging av sykdom. Til sist drøfter vi om det norske alvorlighetskriteriet for helseprioriteringer også kan vaere relevant for prioriteringer utenfor helsevesenet.
In Norway, priority for health interventions is assigned on the basis of three official criteria: health benefit, resources, and severity. Responses to the COVID-19 pandemic have mainly happened through intersectoral public health efforts such as lockdowns, quarantines, information campaigns, social distancing and, more recently, vaccine distribution. The aim of this article is to evaluate potential priority setting criteria for public health interventions. We argue in favour of the following three criteria for public health priority setting: benefit, resources and improving the well-being of the worse off. We argue that benefits and priority to the worse off may reasonably be understood in terms of individual well-being, rather than only health, for public health priority setting. We argue that lessons from the COVID-19 pandemic support our conclusions. Keywords: COVID-19, Prioritarianism, Priority Setting, Public Health, Severity
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.