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Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs

Gui, Jun; Zahedi, Farima; Ortiz, Angelica; Cho, Christina; Katlinski, Kanstantsin V; Alicea-Torres, Kevin; Li, Jinyang; Todd, Leslie; Zhang, Hongru; Beiting, Daniel P; Sander, Cindy; Kirkwood, John M; Snow, Bryan E; Wakeham, Andrew C; Mak, Tak W; Diehl, J Alan; Koumenis, Constantinos; Ryeom, Sandra W; Stanger, Ben Z; Puré, Ellen; Gabrilovich, Dmitry I; Fuchs, Serge Y
Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP). FAP played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.
PMID: 34124690
ISSN: 2662-1347
CID: 5303412

Adverse effects of metal pollutants on reproductive health

Ortiz, Angelica; Chen, Juefei; Costa, Max
Consumption of essential metals is needed for function of certain protein to maintain normal cell integrity. Incorporation and excretion of these metals are governed by the cells, but changes in environmental levels of metals can cause stress. There are areas in which the ambient environment contains non-essential metals that function as toxicants, which alter metal homeostasis thus causing oxidative stress and epigenetic alterations. Ambient air and water, as well as food items in poorly protected areas contain toxic metals, such as arsenic, cadmium, and chromium. Often the exposure to these common metal pollutants is associated with inflammatory diseases and carcinogenesis. However, epidemiology studies and animal experiments demonstrate these metals affect fertility spermatogenesis, sperm concentration, sperm motility, oocyte integrity via epigenetic changes, and contribute to gestational complications. In this review, we present a comprehensive summary of studies demonstrating the detrimental effects of exposure to these metals commonly found in ambient environment on the reproductive health of both males and females.
ISSN: 0972-8228
CID: 4767982

The effect of PM 2.5 from three rural USA areas on inflammatory markers in human keratinocytes [Meeting Abstract]

Sun, H.; Kluz, T.; Matsui, M.; Carle, T.; Gan, D.; Gordon, T.; Ortiz, A.; Costa, M.
ISSN: 0022-202x
CID: 4562122

Toxicity of Carcinogenic Metals to the Brain

Costa, Max; Ortiz, Angelica
ISSN: 2157-2518
CID: 5046712

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles

Ortiz, Angelica; Gui, Jun; Zahedi, Farima; Yu, Pengfei; Cho, Christina; Bhattacharya, Sabyasachi; Carbone, Christopher J; Yu, Qiujing; Katlinski, Kanstantsin V; Katlinskaya, Yuliya V; Handa, Simran; Haas, Victor; Volk, Susan W; Brice, Angela K; Wals, Kim; Matheson, Nicholas J; Antrobus, Robin; Ludwig, Sonja; Whiteside, Theresa L; Sander, Cindy; Tarhini, Ahmad A; Kirkwood, John M; Lehner, Paul J; Guo, Wei; Rui, Hallgeir; Minn, Andy J; Koumenis, Constantinos; Diehl, J Alan; Fuchs, Serge Y
Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.
PMID: 30645975
ISSN: 1878-3686
CID: 4583952

Anti-metastatic functions of type 1 interferons: Foundation for the adjuvant therapy of cancer

Ortiz, Angélica; Fuchs, Serge Y
The anti-tumorigenic effects that type 1 interferons (IFN1) elicited in the in vitro studies prompted consideration of IFN1 as a potent candidate for clinical treatment. Though not all patients responded to IFN1, clinical trials have shown that patients with high risk melanoma, a highly refractory solid malignancy, benefit greatly from intermediate IFN1 treatment in regards to relapse-free and distant-metastasis-free survival. The mechanisms by which IFN1 treatment at early stages of disease suppress tumor recurrence or metastatic incidence are not fully understood. Intracellular IFN1 signaling is known to affect cell differentiation, proliferation, and apoptosis. Moreover, recent studies have revealed specific IFN1-regulated genes that may contribute to IFN1-mediated suppression of cancer progression and metastasis. In concert, expression of these different IFN1 stimulated genes may impede numerous mechanisms that mediate metastatic process. Though, IFN1 treatment is still utilized as part of standard care for metastatic melanoma (alone or in combination with other therapies), cancers find the ways to develop insensitivity to IFN1 treatment allowing for unconstrained disease progression. To determine how and when IFN1 treatment would be most efficacious during disease progression, we must understand how IFN1 signaling affects different metastasis steps. Here, we specifically focus on the anti-metastatic role of endogenous IFN1 and parameters that may help to use pharmaceutical IFN1 in the adjuvant treatment to prevent cancer recurrence and metastatic disease.
PMID: 26822709
ISSN: 1096-0023
CID: 4583962