Targeting of tumor endothelial cells combining 2 Gy/day of X-ray with Everolimus is the effective modality for overcoming clinically relevant radioresistant tumors.
Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS-R, from SAS cells. SAS-R cells continue to proliferate when exposed to fractionated radiation (FR) of 2 Gy/day for more than 30 days in vitro. A xenograft tumor model of SAS-R was also resistant to 2 Gy/day of X-rays for 30 days. The density of blood vessels in SAS-R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS-R cells in vitro. Everolimus with FR markedly reduced SAS and SAS-R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS-R tumor tissues when both Everolimus and radiation were administered. Both CD34-positive and tomato lectin-positive blood vessel densities in SAS-R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus-induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs.
Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan.
Yoshikazu
Y
Kuwahara
Miyuki
M
Mori
Shuji
S
Kitahara
Motoi
M
Fukumoto
Taichi
T
Ezaki
Shiro
S
Mori
Seishi
S
Echigo
Yasuhito
Y
Ohkubo
Manabu
M
Fukumoto
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D000068338:Everolimus; D005260:Female; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; D020123:Sirolimus
Clinically relevant radioresistant; Everolimus; fractionated radiation; thrombus; tumor endothelial cells