Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model

• Published in: International journal of oncology Vol. 49; no. 1; pp. 336 - 342
• Main Authors: KWON, YUN-SUK, LEE, KYU-SHIK, CHUN, SO-YOUNG, JANG, TAE JUNG, NAM, KYUNG-SOO
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: 4T1 orthotopic breast cancer model; Animals; Body Weight - radiation effects; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Care and treatment; Cell growth; Cell Movement - radiation effects; Cell Proliferation - radiation effects; Complications and side effects; Cyclooxygenase 2 - biosynthesis; Development and progression; Female; Gene expression; Gene Expression Regulation, Neoplastic - radiation effects; Genetic aspects; Health aspects; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - radiotherapy; Matrix Metalloproteinase 2 - biosynthesis; Matrix Metalloproteinase 9 - biosynthesis; Medical prognosis; Metastasis; metastatic gene; Mice; Neoplasm Metastasis - pathology; Neoplasm Metastasis - radiotherapy; proton beam; Proton beams; Receptors, Urokinase Plasminogen Activator - biosynthesis; Studies; Urokinase-Type Plasminogen Activator - biosynthesis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Wound healing
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3520

A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis.