Chromosome segregation errors: a double-edged sword - TI Pharma

opportunities for the development of Mps1 inhibitors as tumor-cell specific chemotherapeutics.
In addition to determining the effects of CIN on tumorigenesis, the development of our CiMKi mouse
models (Chapter 3) also provides us with a sophisticated tool to determine the anti-tumor effects
of inhibition of Mps1 kinase activity in vivo. Crossing our CiMKi D637A /CreER strain with a tumorprone
mouse model, such as MMTV-Neu would allow tumor growth in the presence of full Mps1 kinase
activity. Subsequently, we could ablate Mps1 kinase activity through (local) addition of tamoxifen,
which induces expression of kinase-dead Mps1 (D637A), and determine tumor regression following
complete tumor formation. In addition, we could use our CiMKi models to determine effects of Mps1
inhibition on healthy tissues through systemic application of tamoxifen.
3.3 How do anti-mitotic drugs kill tumor cells?
Although in vitro experiments show preferential killing of tumor cells following Mps1
inhibition (Chapter 5, 6), the question remains whether similar results will be found in vivo.
The percentage of mitotic cells in tumors is significantly lower than the percentage found in
cell culture 612 . This indicates that drugs, specifically designed to affect mitotic progression
of tumor cells, might not be as effective in vivo as anticipated from in vitro experiments.
As described in Chapter 7, taxanes induce cell death in tumors in vivo, but do this independently of
clear effects on mitotic progression. These data are in line with previous results found using intravital
imaging in mice and immunohistochemistry analysis of patient tumors treated with taxanes 597-599 . This
indicates that taxanes might not be so successful due to their anti-mitotic effects, but rather kill tumor
cells through other means. Taxanes might exert anti-tumor effects through activation of the patients’
immune system 615 or inhibition of blood vessel formation in the tumor 612 for example. Another
hypothesis is that only a handful of cells in the tumor die due to taxane-induced mitotic defects and
that their death induces some sort of butterfly effect on the rest of the tumor cells, for example
through release of pro-inflammatory cytokines or release of pro-apoptotic signals to their neighbors 612 .
In conclusion, data from us (Chapter 7) and others 597 indicate that classical anti-mitotic drugs that
were initially thought to act by perturbation of spindle assembly could induce tumor cell death in
human patients via a different mechanism than what has been observed in cell culture. Nonetheless,
two studies have revealed anti-tumor activity of Mps1 inhibitors in vivo 176,578 and our data show that
extremely low levels of Mps1 inhibitors could be sufficient to specifically kill cancer cells (Chapter 6).
Eventually, cancer cells need to divide to form a tumor and at some stage in tumor development these
dividing cells should be targetable in vivo as well.
4. Concluding remarks
Tumors are extremely heterogeneous, which makes it difficult to determine which
cancer cell features are consequences and which are actual initiators of tumorigenesis.
Even if CIN turns out to be a mere consequence of cancer progression, we and others
have shown that chromosome segregation errors can definitely provide the cancer cell
with more evolutionary benefits, which could eventually enhance tumor progression.
More importantly, we show that CIN might be useful as an exploitable tumor-specific trait in anticancer
therapy, since healthy cells are rather insensitive to Mps1 inhibition. Although it remains
unknown whether CIN can initiate tumorigenesis, it should be noted that chemotherapeutics that
induce excessive CIN in tumors could promote tumorigenesis in healthy cells in the long run. As such,
future research in mice should focus on the long-term effects of Mps1 inhibition on healthy cells in
vivo.
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Discussion
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