Correlation Between Tumor Growth Delay and Expression of Cancer and Host VEGF, VEGFR2, and Osteopontin in Response to Radiotherapy

Abstract

Purpose-to determine late effects of radiotherapy on the VEGF, VEGFR2 and OPN expression in cancer and stromal cells.Methods and Materials-LS174T xenografted athymic mice were used as a tumor model. Radiation was delivered in two equivalent fractionation schemes: 5×7 Gy and 1×20 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-sized tumors in the 5×7 Gy group. Host VEGF and OPN levels were directly proportional to tumor doubling time (T D ) and were independent of the fractionation scheme. Host and cancer cell VEGFR2 levels in tumor were also directly related to the tumor response to radiotherapy.Conclusion-Upregulated VEGFR2 in cancer cells suggest paracrine signaling in the VEGFR2 pathway of cancer cells as the factor contributing to the radiotherapy 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 may contribute to the failure of radiotherapy by escalating the rate of vascular repair. Co-expression of host OPN and VEGF, two factors closely associated with angiogenesis, indicate that OPN can serve as a surrogate marker of the tumor recovery after radiotherapy. Taken together these results strongly support the notion that to achieve optimal therapeutic outcome, the scheduling of radiation 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 the tumor regrowth.

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

“…However, how osteopontin is associated with biological radiation resistance is uncertain. As osteopontin is thought to be an indicator of endogenous tissue hypoxia response (Bache et al 2006;Hahne et al 2013;Le et al 2003;Said et al 2007;Yang et al 2012) and tumor regrowth after radiotherapy (Solberg et al 2008), we suggest that elevated osteopontin expression in cervical cancer is related to radiation resistance and this is partly due to hypoxia, which affects radiosensitivity- (Avanzo et al 2010;Bouchat et al The 5-year progression-free survival (PFS) rates were 92.42% and 63.42%, respectively, in patients with low osteopontin expression (n=62) and high osteopontin expression (n=49). There was a significant difference in the overall survival rate between the two groups (p<0.001).…”

Combining angiogenesis inhibition and radiotherapy: A double-edged sword

“…Apart from direct effects, several studies have shown that irradiation can also indirectly influence angiogenesis by inducing the expression of pro-angiogenesis growth factors like VEGF by tumor cells or other cells that reside in the tumor stroma (Solberg et al, 2008;Tsai et al, 2007). For example, Nozue et al found a significant increase in VEGF expression after radiotherapy in rectal carcinomas (Nozue et al, 2001).…”

HAb18G/CD147 Promotes Radioresistance in Hepatocellular Carcinoma Cells: A Potential Role for Integrin β1 Signaling

“…Postirradiation evaluations of VEGF/ VEGFR2 may provide insights into the tumor response and can aid in planning the follow-up treatment (43). Radiationenhanced activation of MMPs may promote tumor progression by decreasing apoptosis, stimulating proliferation, and increasing the angiogenic and invasive potentials (44,45).…”