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Radiation therapy to a primary tumor accelerates metastatic growth in mice
K Camphausen1, M A Moses, W D Beecken
1Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The surgical removal of a primary tumor can result in the rapid growth of metastases. The production of angiogenesis inhibitors by the primary tumor is one mechanism for the inhibition of metastatic tumor growth. The effect of curative radiotherapy to a primary tumor known to make an inhibitor of angiogenesis and the effects on distant metastases has not been studied. We here show that the eradication of a primary Lewis lung carcinoma (LLC-LM), which is known to generate angiostatin, is followed by the rapid growth of metastases that kill the animal within 18 days after the completion of radiation therapy. The right thighs of C57BL/6 mice (n = 25) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of five groups: no irradiation, 40 Gy in one fraction, 30 Gy in one fraction, 40 Gy in two 20 Gy fractions, or 50 Gy in five 10 Gy fractions. Tumors were clinically eradicated in each treatment group. All of the surviving animals became dyspneic and were killed within 14-18 days after the completion of radiation therapy. Examination of their lungs revealed >46 (range, 46-62) surface metastases in the treated animals compared with 5 (range, 2-8) in the untreated animals. The lung weights had increased from 0.2 g (range, 0.19-0.22 g) in the controls to 0.58 g (range 0.44-0.84) in the experimental animals. The most effective dose regimen was 10 Gy per fraction for five fractions, and serial experiments were conducted with this fractionation scheme. Complete response of the primary tumor was seen in 25 of 35 (71%) mice. The average weight of the lungs in the nonirradiated animals was 0.22 g (range, 0.19-0.24 g) and in the irradiated animals was 0.66 g (range, 0.61-0.70 g). The average number of surface metastases increased from five per lung (range, 2-13) in the control animals to 53 per lung (range, 46-62) in the irradiated animals. Both differences were statistically significant with P < 0.001. If the nontumor-bearing leg was irradiated or the animals were sham-irradiated, no difference in the number of surface metastases or lung weights was observed between the control group and the treated group. Urinary levels of matrix metalloproteinase 2, the enzyme responsible for angiostatin processing in this tumor model, were measured and correlated with the viability and size of the primary tumor. Administration of recombinant angiostatin prevented the growth of the metastases after the treatment of the primary tumor. In this model, the use of radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining angiogenesis inhibitors with radiation therapy may control distant metastases.
Insights
Curative radiotherapy eradicating Lewis lung carcinoma (LLC-LM) primary tumors, which produce angiostatin, paradoxically accelerates the growth of distant metastases. Combining radiation with angiogenesis inhibitors may be crucial for controlling metastatic spread.
Area of Science:
- Oncology
- Radiotherapy
- Cancer Metastasis
Background:
- Primary tumor removal can trigger rapid metastasis growth.
- Primary tumors can produce angiogenesis inhibitors, like angiostatin, to suppress metastasis.
- The impact of radiotherapy on primary tumors producing angiogenesis inhibitors and its effect on distant metastases remains unstudied.
Purpose of the Study:
- To investigate the effect of curative radiotherapy on a primary Lewis lung carcinoma (LLC-LM) that produces angiostatin.
- To determine the subsequent impact on distant lung metastases.
- To explore the potential of combining radiotherapy with angiogenesis inhibitors.
Main Methods:
- Lewis lung carcinoma (LLC-LM) cells were implanted in C57BL/6 mice.
- Primary tumors were treated with various radiotherapy regimens (e.g., 40 Gy, 30 Gy, 50 Gy in fractions).
- Tumor eradication, lung metastasis, lung weight, and urinary matrix metalloproteinase 2 levels were assessed. Recombinant angiostatin was administered to some groups.
Main Results:
- Curative radiotherapy eradicated primary LLC-LM tumors but led to rapid growth of lung metastases (average 53 vs. 5 metastases).
- Irradiated mice showed significantly increased lung weight and mortality within 14-18 days post-treatment.
- Administration of recombinant angiostatin prevented metastasis growth after primary tumor treatment.
Conclusions:
- Eradication of an angiostatin-producing primary tumor via radiotherapy accelerates the growth of dormant lung metastases.
- This suggests that radiotherapy alone may inadvertently promote metastatic disease in certain contexts.
- Combining radiotherapy with angiogenesis inhibitors is a potential strategy to control distant metastases.