Abstract
Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.
Highlights
Radiation therapy is a commonly used curative treatment modality for cancer patients
Senescent cells contribute to further injury through depletion of normal tissue stem cells and via expression of the senescence associated secretory phenotype (SASP), a complex mixture of inflammatory, immunomodulatory, angiogenic, and mitogenic molecules secreted by senescent cells [11,12,13,14,15,16,17,18]
To characterize the time dependence of radiationinduced normal tissue senescence in lung, mice were exposed to 5 daily fractions of 6 Gy (6Gyx5) thoracic IR and the number of cells exhibiting SA-β-Galactosidase activity was evaluated at 2, 4, and 8 weeks after IR (n = 10 per group)
Summary
Radiation therapy is a commonly used curative treatment modality for cancer patients. Irradiation (IR) of tumors typically results in the simultaneous exposure of surrounding normal tissue to radiation, resulting in a host of changes such as oxidative stress, inflammation, activation of cytokine signaling, and extracellular matrix deposition [1,2,3]. These changes in normal tissue are implicated in late injury after radiotherapy. Expression of the SASP by senescent cells has been shown to propagate normal tissue injury and stimulate tumor growth [19]. Senescence in lung has been demonstrated to contribute to lung injury [3], and targeting senescence with agents that prevent senescence after injury or that selectively clear senescent cells (senolytic) have been shown to reduce lung fibrosis after radiation [3, 8, 10, 20, 21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
