CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma.
Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.
Monnier
Yan
Y
Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologie, Faculty of Biology and Medicine, University of Lausanne, Switzerland.
Farmer
Pierre
P
Bieler
Gregory
G
Imaizumi
Natsuko
N
Sengstag
Thierry
T
Alghisi
Gian Carlo
GC
Stehle
Jean-Christophe
JC
Ciarloni
Laura
L
Andrejevic-Blant
Snezana
S
Moeckli
Raphael
R
Mirimanoff
René-Olivier
RO
Goodman
Simon L
SL
Delorenzi
Mauro
M
Rüegg
Curzio
C
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000528:radiation effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055515:Cysteine-Rich Protein 61; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D017154:Stromal Cells / Q000473:pathology / Q000528:radiation effects
C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5