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 tumour. Show all posts
Showing posts with label tumour. Show all posts
Immune response to cancer cells (and maybe senescent cells)
Since any immune response to the presence of senescent cells may possibly be similar to that of cancer cells, the following is a brief outline describing the key points in the removal process (Ullrich et al, 2007, Vulink et al, 2008, Wesa and Storkus, 2008, Chan and Housseau, 2008).
Dendritic cells are antigen-presenting cells found in all tissues of the body and are crucial for stimulating a naïve T-lymphocyte response in the removal of tumour cells.
In the presence of tumour cells, dendritic cells capture (by engulfing portions of the tumour cell) and process tumour-specific molecules (antigens) so that they become presented on their cell surface. Dendritic cells start to mature as they migrate to the lymph nodes, a process which enables dendritic cells to present the tumour information. The maturation process is needed as additional co-stimulatory molecules are required so that they can be recognised by other immune cells. When mature dendritic cells reach the lymph nodes, they interact with cytotoxic T-lymphocytes (CTLs), and pass on the tumour information, causing CTLs to become activated and consequently proliferate. The large numbers of CTLs then circulate the body, recognising the tumour-specific antigens, binding to them and destroying tumour cells by the release of enzymes.
If a cancer cell (or a senescent cell) is not removed by the immune system, then something isn’t working as it should. From the brief overview above, there are a number of points between cell recognition and removal that could have failed. These are:
(1) Dendritic cells did not recognise the cancer/senescent cell.
(2) The dendritic cells did not display cancer/senescent specific markers on it’s surface.
(3) Lymphocytes were not activated in response to dendritic cells.
The changes which occur as we age which may have an impact on the removal of tumour cells/senescent cells will be discussed next.
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Review Paper: Physiological and pathological consequences of cellular senescence
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