Locally ablative radio therapy of a primary human small cell lung cancer tumor decreases the number of spontaneous metastases in two xenograft models

Publication date: Available online 6 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Thorsten Frenzel, Jordana Siekmann, Carsten Grohmann, Ursula Valentiner, Rüdiger Schmitz, Kristoffer Riecken, Boris Fehse, Udo Schumacher, Tobias Lange, Andreas Krüll
IntroductionCancer patients mainly die from distant metastases, for which small cell lung cancer (SCLC) serves as an instructive example. As it is still under debate whether radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT) or chemotherapy (ChT) may promote metastatic spread, we investigated the influence of these treatments on SCLC metastases in two xenograft models.Methods and materials1 x 10⁶ human SCLC cells (OH1, H69) were subcutaneously injected into SCID mice to form a local primary tumor node at the lower trunk. RT, OP, RChT, or ChT were started after development of palpable tumors. ChT was given as a single intraperitoneal injection of cisplatin. RT was 5 x 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control groups A) and at the end of the experiment (control groups B). Pro-apoptotic, anti-proliferative, anti-angiogenic, and hypoxic effects were assessed by Feulgen, Ki-67, S1P1 receptor, and HIF1α staining, respectively. Quantitative Alu-PCR was used to determine circulating tumor cells (CTCs) in the blood, and disseminated tumor cells (DTCs) in the lungs, bone marrow, liver, and brain.ResultsIn both xenograft models, RT and RChT abrogated local tumor growth indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination, but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in case of relapse-free surgery, similar effects could be achieved by OP.ConclusionOur models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regards to suppression of CTCs and DTCs.

Teaser

The influence of radiotherapy, surgery, chemotherapy, and radio-chemotherapy on local primary tumor growth and on spontaneous distant metastasis formation was investigated in two human small cell lung cancer xenograft mouse models. Local tumor control was most important to suppress metastasis formation. Most interestingly, radiotherapy was not only locally ablative and prevented spontaneous distant metastasis formation over time, but even reduced the metastatic cell load in distant organs pre-existing at the time of therapy induction.


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