Senescence-associated tumor growth is promoted by 12-Lipoxygenase

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.

Senescent cell-derived vaccines: a new concept towards an immune response against cancer and aging?

“…In a cancer framework, Patil and colleagues recently demonstrated that treatment of irradiated mice with a small molecule that tackles senescent cells (the senolytic agent ABT-737) was sufficient to reduce radiation-enhanced tumor growth through the control of the expression of 12-lipoxygenase (12-LOX), a molecule mediating the deleterious effects of senescence. These data demonstrate how radiation-induced senescence could support tumor growth, and identified a key component (12-LOX) of the oncogenic microenvironment [ 40 ]. Another compound, ABT-263, has demonstrated powerful senolytic activity against senescent breast cancer cells generated by radiation or chemotherapy [ 41 ].…”

Lipoxygenases at the Intersection of Infection and Carcinogenesis

“…Combination of ALOX12 inhibitors (baicalein and BMD122) and radiation therapy have synergistic inhibitory effects on the growth of LNCaP and PC-3 prostate cancer cells as well as prostate cancer xenografts in SCID mice [237]. In a syngeneic tumor model of non-small cell lung cancer and melanoma, ALOX12 inhibition was showed to mitigate the effect of pre-radiation on the growth of pulmonary tumor nodules [238].…”

An untapped window of opportunity for glioma: targeting therapy-induced senescence prior to recurrence

“…Radiation is known to induce a pro-inflammatory phenotype in microglia through activation of NF- B and mitogen-activated protein kinase (MAPK) pathways, resulting in increased cytokine secretion and neuronal apoptosis 79 . Radiation also induces senescence in tumor-associated macrophages (TAMs) 80 , while aiding in their recruitment in addition to that of activated peripheral monocytes and other immune cells 81 , both in non-glioma cancer models. Of note, the relative burden of therapy-induced senescence as a percentage of each cell population has yet to be determined, particularly in patient-derived specimens.…”