Abstract
The ectonucleoside triphosphate diphosphohydrolase (CD39)/5′ ectonuclotidase (CD73)-dependent purinergic pathway emerges as promising cancer target. Yet, except for own previous work revealing a pathogenic role of CD73 and adenosine in radiation-induced lung fibrosis, the role of purinergic signaling for radiotherapy outcome remained elusive. Here we used C57BL/6 wild-type (WT), CD39 knockout (CD39−/−), and CD73 knockout (CD73−/−) mice and hind-leg tumors of syngeneic murine Lewis lung carcinoma cells (LLC1) to elucidate how host purinergic signaling shapes the growth of LLC1 tumors to a single high-dose irradiation with 10 Gy in vivo. In complementary in vitro experiments, we examined the radiation response of LLC1 cells in combination with exogenously added ATP or adenosine, the proinflammatory and anti-inflammatory arms of purinergic signaling. Finally, we analyzed the impact of genetic loss of CD39 on pathophysiologic lung changes associated with lung fibrosis induced by a single-dose whole-thorax irradiation (WTI) with 15 Gy. Loss of CD73 in the tumor host did neither significantly affect tumor growth nor the radiation response of the CD39/CD73-negative LLC1 tumors. In contrast, LLC1 tumors exhibited a tendency to grow faster in CD39−/− mice compared to WT mice. Even more important, tumors grown in the CD39-deficient background displayed a significantly reduced tumor growth delay upon irradiation when compared to irradiated tumors grown on WT mice. CD39 deficiency caused only subtle differences in the immune compartment of irradiated LLC1 tumors compared to WT mice. Instead, we could associate the tumor growth and radioresistance-promoting effects of host CD39 deficiency to alterations in the tumor endothelial compartment. Importantly, genetic deficiency of CD39 also augmented the expression level of fibrosis-associated osteopontin in irradiated normal lungs and exacerbated radiation-induced lung fibrosis at 25 weeks after irradiation. We conclude that genetic loss of host CD39 alters the tumor microenvironment, particularly the tumor microvasculature, and thereby promotes growth and radioresistance of murine LLC1 tumors. In the normal tissue loss of host, CD39 exacerbates radiation-induced adverse late effects. The suggested beneficial roles of host CD39 on the therapeutic ratio of radiotherapy suggest that therapeutic strategies targeting CD39 in combination with radiotherapy have to be considered with caution.
Highlights
Radiotherapy (RT) alone or in combination with surgery and chemotherapy is a central component of curative or palliative treatment for many cancer patients
LLC1 tumor cells were subcutaneously implanted onto the hind-leg of C57BL/6 WT mice, CD39deficient mice (CD39−/−), or CD73-deficient mice (CD73−/−) (Figures 1, 2)
Characterization of purinergic signaling in the tumor cells revealed that LLC1 cells uncovered a CD39 gene expression that was not altered by irradiation, but cell surface staining revealed that the LLC1 cells did neither express CD39, CD73, nor the ATP receptor P2X7R (Figure 1B), nor did irradiation with 5 or 10 Gy induce an expression of these markers
Summary
Radiotherapy (RT) alone or in combination with surgery and chemotherapy is a central component of curative or palliative treatment for many cancer patients. Patients suffering from advanced non–small cell lung cancer (NSCLC) receive standard treatment with fractionated RT to the thoracic region or concurrent platinum-based radiochemotherapy (RCT), yielding local control rates of 40–66% [1,2,3]. Intratumoral heterogeneity and high intrinsic or acquired radioresistance can lead to relapse, whereas a pronounced radiosensitivity of coirradiated normal lung tissue causes adverse effects in sensitive patients, thereby limiting the application of curative RT doses and therapy intensification efforts of RT or RCT [3, 4]. Current efforts to improve RT outcome aim at combining highly conformal RT with molecularly tailored treatments to increase efficacy of tumor cell killing or reduce adverse effects to normal tissues, respectively. For improving the therapeutic gain of RT, such combinatorial treatments will ideally sensitize the tumor cells only, or at least more substantially than the coirradiated normal tissues or prevent or reduce acute and late toxicities to normal tissues without protecting the tumor
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