Correlation between tumor growth delay and expression of cancer and host VEGF, VEGFR2, and osteopontin in response to radiotherapy.
OBJECTIVE
To determine the late effects of radiotherapy (RT) on vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and osteopontin (OPN) expression in cancer and stromal cells.


METHODS
LS174T xenografted athymic mice were used as a tumor model. Radiation was delivered in two equivalent fractionation schemes: 5 x 7 Gy and 1 x 20 Gy, the latter at two dose rates.


RESULTS
Tumor growth arrest was similar in all treatment groups, with the exception of a better response of small-size tumors in the 5 x 7-Gy group. The host VEGF and OPN levels were directly proportional to the tumor doubling time and were independent of the fractionation scheme. The host and cancer cell VEGFR2 levels in tumor were also directly related to the tumor response to RT.


CONCLUSIONS
Upregulated VEGFR2 in cancer cells suggest paracrine signaling in the VEGFR2 pathway of cancer cells as the factor contributing to RT failure. The transient activation of the host VEGF/VEGFR2 pathway in tumor supports the model of angiogenic regeneration and suggests that radiation-induced upregulation of VEGF, VEGFR2, and downstream proteins might contribute to RT failure by escalating the rate of vascular repair. Coexpression of host OPN and VEGF, two factors closely associated with angiogenesis, indicate that OPN can serve as a surrogate marker of tumor recovery after RT. Taken together, these results strongly support the notion that to achieve optimal therapeutic outcomes, the scheduling of RT and antiangiogenic therapies will require patient-specific post-treatment monitoring of the VEGF/VEGFR2 pathway and that tumor-associated OPN can serve as an indicator of tumor regrowth.
Solberg
Timothy D
TD
University of Nebraska Medical Center, Omaha, NE, USA.
Nearman
Jessica
J
Mullins
John
J
Li
Sicong
S
Baranowska-Kortylewicz
Janina
J
D000230:Adenocarcinoma; D000818:Animals; D002455:Cell Division / Q000502:physiology* / Q000528:radiation effects; D015179:Colorectal Neoplasms; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D053495:Osteopontin / Q000235:genetics* / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000532:radiotherapy; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000528:radiation effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000528:radiation effects
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D053495:Osteopontin; D040301:Vascular Endothelial Growth Factor Receptor-2