Download Radiation-induced collateral damage: impact on metastasis

Oncothesis
Radiation-induced collateral
damage: impact on metastasis
L. Feys, PhD1, O. De Wever, PhD1, M. Bracke, MD, PhD1
Experimental conditions show that radiotherapy-induced damage of normal tissues induces a prometastatic environment; and our research focussed on the factors associated with these pro-metastatic
effects, which can be used as potential therapeutic targets.
(Belg J Med Oncol 2016;10(3):105-107)
Introduction
Recent studies show that radiation treatment of cancer inhibits primary tumour growth but has disturbing side effects which can contribute to invasion and
metastasis of the tumour.1,2 Both cancer and host
cells may contribute to these effects.3,4 For example,
in breast cancer the lung is an important organ that
can suffer from collateral irradiation damage. The
potential impact of this damage on invasion and metastasis needs to be further investigated to improve
patient outcome.
Therefore, our fi rst aim was to develop an in vivo
model where follow-up of tumour progression was
possible, taking the 3R’s (replacement, reduction
and refi nement) of animal welfare into account.
We found that a bioluminescent cancer cell model
had the same characteristics as the corresponding
parental cancer cell, making it an ideal tool to use for
further in vitro and in vivo studies. This in vivo model
allowed us to investigate the effects of radiotherapy
on host cells and their contribution to pro-invasive
and pro-metastatic side effects. Our findings
emphasise the urgency to develop effective drugs
which can be combined efficiently with radiotherapy
(RT) in order to prevent the therapy-induced spread
of cancer cells.
1
It has been shown that irradiation (IR) can cause late
secondary malignancies and tumour bed IR can promote metastasis, but experimental set-ups to show
the impact of IR on the formation of a metastasisreceptive microenvironment are lacking. We developed a syngeneic breast cancer model where partial
irradiation of healthy mouse lung increases metastatic load and size in both lungs.
In our research we irradiated healthy lung cells/tissue and studied its impact on metastasis-associated cellular activities of triple-negative breast cancer
(TNBC) cells in vitro and in vivo. We made use of in
vitro models to mimic the metastatic cascade and to
reveal underlying molecular pathways. We showed
that irradiation of normal lung epithelial cells causes
DNA double-strand breaks, which lead to upregulation of proteins involved in cell cycle arrest and
senescence. This activates cell signalling cascades
which promote secretion of chemokine C-X-C ligand 12/stromal-derived factor-1 (CXCL12/SDF-1)
and macrophage migration inhibitory factor (MIF).
These chemokines are responsible for activation of
the chemokine C-X-C receptor 4 (CXCR4) pathway
in triple-negative breast cancer cells, resulting in a
pro-metastatic character. We also showed that when
mimicking the in vivo situation, there is not only
a local, target related effect, but also a distant offtarget related increase in breast cancer cell coloni-
Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium.
Please send all correspondence to: L. Feys, PhD, Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, Ghent, Belgium, email: [email protected].
Conflict of interest: This research was supported by Stichting Emmanuel van der Schueren (Kom op tegen Kanker) and Stichting tegen Kanker.
L. Feys was supported by Association Research Fund of Ghent University and HoGent (05V03011).
Keywords: bioluminescence, CXCR4, radiotherapy, triple-negative breast cancer.
Belgian Journal of Medical Oncology
105
Volume 10, Issue 3, May 2016
Actions
Bronchial epithelial cell
irradiation
bronchial
epithelial cell
breast
cancer cell
lncreased CXCL12
and MIF secretion
CXCL12
MIF
CXCR4 pathway activation
in arriving cancer cells
CXCR4
lncreased: - Cell spread
- Proliferation
- Migration
- Extravasation
lncreased lung metastasis
Figure 1. Schematic figure showing the multiple processes occurring after irradiation of healthy lung cells/ tissue.
CXCL12 (chemokine C-X-C motif ligand 12), MIF (macrophage migration inhibitory factor) and CXCR4 (chemokine C-X-C
motif receptor 4).
Belgian Journal of Medical Oncology
Volume 10, Issue 3, May 2016
106
3
Oncothesis
Key messages for clinical practice
1.
Radiation induces secretion of SDF-1 and MIF in healthy tissue.
2.
SDF-1 and MIF activate CXCR4 receptor on triple-negative breast cancer cells.
3.
CXCR4 activation induces tumour metastasis.
sation of the whole lung tissue. This means that a
small volume of irradiated lung released SDF-1 and
MIF to promote cancer cell growth outside the irradiated area. When we added supernatant of irradiated lung epithelial cells or recombinant SDF-1 and
MIF to breast cancer cells, we observed increased
cell migration, growth and cellular dedifferentiation
into a more mesenchymal phenotype (Figure 1). In
vivo experiments where we performed partial irradiation of mice lungs by using the small animal research radiation platform (SARRP, Xstrahl®, Surrey,
UK) showed an increase in metastases and metastatic growth compared to unirradiated lungs. Further
analysis revealed that disruption of the CXCL12/
CXCR4 and MIF/CXCR4 interaction is essential for
breast cancer cells to return to their ‘normal’ phenotype. When blocking the CXCR4 receptor in vivo,
a decrease of metastatic load is observed.
We conclude that more patient relevant preclinical
models and clinical studies should be developed to
closely recapitulate the clinical features and to study
the breast cancer response upon the use of MIF and
CXCL12 inhibitors combined with RT, especially as
neoadjuvant treatment for TNBC patients.
production cause attraction and activation of stem
cells (bone marrow derived), endothelial progenitor
cells, immune cells and local stromal cells, which
creates a more suitable ‘soil’ in the irradiated lung.5-8
These findings allow us to explore the effects of RT
on metastasis formation and contribute to the search
for anti-metastatic strategies.
References
1. Paquette B, Therriault H, Desmarais G, et al. Radiation-enhancement of
MDA-MB-231 breast cancer cell invasion prevented by a cyclooxygenase-2
inhibitor. Br J Cancer. 2011;105(4):534-41.
2. Bouchard G, Bouvette G, Therriault H, et al. Pre-irradiation of mouse mammary gland stimulates cancer cell migration and development of lung metastases. Br J Cancer. 2013;109(7):1829-38.
3. Kuonen F, Laurent J, Secondini C, et al. Inhibition of the Kit ligand/c-Kit axis
attenuates metastasis in a mouse model mimicking local breast cancer relapse
after radiotherapy. Clin Cancer Res. 2012;18(16):4365-74.
4. Barker HE, Paget JT, Khan AA, et al. The tumour microenvironment after
radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer.
2015;15(7):409-25.
5. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453-8.
6. Teicher B, Fricker S. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin
Cancer Res. 2010;16(11):2927-31.
Conclusion
Our results show that accidental IR of normal lung
tissue during breast cancer RT enhances the formation of metastatic niche in the lungs and the persistent growth of metastasis. Local CXCL12 and MIF
7. Verjans E, Noetzel E, Bektas N, et al. Dual role of macrophage migration
inhibitory factor (MIF) in human breast cancer. BMC Cancer. 2009;9:230.
8. Feys L, Descamps B, Vanhove C, et al. Radiation-induced lung damage
promotes breast cancer lung-metastasis through CXCR4 signalling. Oncotarget. 2015;6(29):26615-32.
All published BJMO articles are available on our website:
www.ariez.com
as well as all published articles from our other medical journals
Belgian Journal of Medical Oncology
107
Volume 10, Issue 3, May 2016