Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer

Stabile, Laura P.; Farooqui, Mariya; Kanterewicz, Beatriz; Abberbock, Shira; Kurland, Brenda F.; Diergaarde, Brenda; Siegfried, Jill M.

doi:10.1016/j.jtho.2017.11.126

Cited by 26 publications

(22 citation statements)

References 60 publications

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“…Conversely, in NNK treated mice that received the aromatase inhibitor anastrozole, a significant reduction in pulmonary TAMs was found, which were found to be aromatase and ERβ positive (67). Addition of a non-steroidal anti-inflammatory agent to anastrozole was shown to further reduce TAM recruitment in this model (67). A limitation to the studies in the NNK model of lung cancer is that TAM expression was assessed through IHC and M1/M2 phenotypes were not distinguished.…”

Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 92%

“…In lung preneoplasias that developed after NNK plus E2 treatment, a significant increase in inflammatory markers and VEGF, an E2 reponsive gene and regulator of macrophage recruitment and the M1/M2 macropahge switch, was found compared to control (67). Conversely, in NNK treated mice that received the aromatase inhibitor anastrozole, a significant reduction in pulmonary TAMs was found, which were found to be aromatase and ERβ positive (67). Addition of a non-steroidal anti-inflammatory agent to anastrozole was shown to further reduce TAM recruitment in this model (67).…”

Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 97%

“…Fulvestrant was also shown to prevent lung tumorigenesis in mice exposed to the tobacco carcinogen, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), suggesting possible value for the use of antiestrogens as protective agents against smoking induced lung cancer (66). Similarly, aromatase inhibitors, including anastrozole and exemestane, were also effective at inhibiting tumor growth and tumor incidence in multiple NSCLC murine models (66)(67)(68). Furthermore, the combinatorial use of both fulvestrant and anastrozole demonstrated a synergistic, inhibitory effect on both initiation, and progression of lung tumors in the NNK lung cancer model (66).…”

Section: Preclinical Studiesmentioning

confidence: 99%

“…In vivo studies using the tobacco carcinogen NNK induced lung cancer model demonstrated that administration of E2 in mice increased pulmonary TAM infiltration (67). In lung preneoplasias that developed after NNK plus E2 treatment, a significant increase in inflammatory markers and VEGF, an E2 reponsive gene and regulator of macrophage recruitment and the M1/M2 macropahge switch, was found compared to control (67). Conversely, in NNK treated mice that received the aromatase inhibitor anastrozole, a significant reduction in pulmonary TAMs was found, which were found to be aromatase and ERβ positive (67).…”

Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 99%

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Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.

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Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 92%

Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 97%

Section: Preclinical Studiesmentioning

confidence: 99%

Section: Estrogen Modulates Tumor Infiltrating Myeloid Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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“…Furthermore, E2 enhanced M2 macrophage secretion of vascular endothelial growth factor (VEGF), an identified mediator of M2 macrophage recruitment [ 81 , 82 ]. E2 has been shown to also upregulate VEGF expression and pulmonary macrophage content in the lungs of mice exposed to a tobacco carcinogen [ 83 ]. Evaluation of E2-mediated tumor growth in a HGSOC murine model showed that E2 not only enhanced the growth of ER-negative xenografts, but also increased M2 TAM infiltration compared to untreated ovariectomized mice [ 54 ].…”

Section: Estrogen Receptor and Aromatase Expression And Estrogen-mmentioning

confidence: 99%

The Role of the Estrogen Pathway in the Tumor Microenvironment

Rothenberger

Somasundaram

Stabile

2018

IJMS

159

115

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Estrogen receptors are broadly expressed in many cell types involved in the innate and adaptive immune responses, and differentially regulate the production of cytokines. While both genomic and non-genomic tumor cell promoting mechanisms of estrogen signaling are well characterized in multiple carcinomas including breast, ovarian, and lung, recent investigations have identified a potential immune regulatory role of estrogens in the tumor microenvironment. Tumor immune tolerance is a well-established mediator of oncogenesis, with increasing evidence indicating the importance of the immune response in tumor progression. Immune-based therapies such as antibodies that block checkpoint signals have emerged as exciting therapeutic approaches for cancer treatment, offering durable remissions and prolonged survival. However, only a subset of patients demonstrate clinical response to these agents, prompting efforts to elucidate additional immunosuppressive mechanisms within the tumor microenvironment. Evidence drawn from multiple cancer types, including carcinomas traditionally classified as non-immunogenic, implicate estrogen as a potential mediator of immunosuppression through modulation of protumor responses independent of direct activity on tumor cells. Herein, we review the interplay between estrogen and the tumor microenvironment and the clinical implications of endocrine therapy as a novel treatment strategy within immuno-oncology.

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