While the history of research on cell senescence counts for more than half a century, only in the last 10 years the
functional relevance of cell senescence
in vivo
was established. The irreversible cell cycle arrest in OIS cells makes it
an ideal mechanism to prevent tumour formation following
oncogene activation, and in the first functional in vivo studies, cell senescence was established as a tumour
suppressor mechanism. OIS has been shown to be important
for preventing lymphoma
development and contribute to response to therapy.
Using transgenic mice models to bypass the senescence
response to oncogenic N-Ras resulted in the development of invasive T-cell
lymphomas, whereas control mice only develop non-lymphoid neoplasia at a much
later time point. Another mouse
model using inducible K-ras was used to make pre-malignant
lesions that can develop into malignant tumours in lung and pancreas. In
these models, biomarkers of
cell senescence were
predominantly identified in
the pre- malignant lesions
but were lost once tumours
developed. To investigate OIS in vivo, a number of studies have focused on human
nevi (moles), which are benign tumours of melanocytes that frequently harbor
oncogenic mutations of BRAF. The congenital nevi stained positive
for markers of OIS, but not DNA damage in this instance. BrafE600V, which is present in the nevi, induced
p16(INK4a) expression in growth-arrested melanocytes both in vitro and in situ. In contrast, another study in
premalignant melanocytic lesions did show the presence of DNA damage foci, primarily located at
telomeric regions as well as the p16(INK4a) expression. In addition
to activating mutations
in oncogenes, cell senescence can be induced as a result of loss of tumor
suppressor Pten in the prostate.
Therefore, these combined studies clearly demonstrate that cell senescence acts as a potent tumor suppressor mechanism that prevents the development
of multiple malignancies.
A blog for those interested in the physiological and pathological impact of senescent cells.
Showing posts with label tumor. Show all posts
Showing posts with label tumor. Show all posts
Enhanced killing of therapy-induced senescent tumor cells by oncolytic Measles vaccine viruses
ABSTRACT
Therapy-induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS has emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity in vivo or even secrete tumor-promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence-inducing drugs was explored. As a model we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell-associated and released infectious MeV particles. In summary, we show as a proof-of-concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach.
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