{"id":823,"date":"2024-10-31T06:00:40","date_gmt":"2024-10-31T06:00:40","guid":{"rendered":"http:\/\/socmexfito.org\/?p=823"},"modified":"2024-10-31T06:00:40","modified_gmt":"2024-10-31T06:00:40","slug":"likely-this-downregulation-is-either-due-to-stimulated-removal-of-dna-from-the-cytosol-or-downregulation-of-the-cgas-sting-signaling-pathway-in-the-cancer-cells-within-the-tumor","status":"publish","type":"post","link":"https:\/\/socmexfito.org\/?p=823","title":{"rendered":"\ufeffLikely, this downregulation is either due to stimulated removal of DNA from the cytosol or downregulation of the cGAS-STING signaling pathway in the cancer cells within the tumor"},"content":{"rendered":"

\ufeffLikely, this downregulation is either due to stimulated removal of DNA from the cytosol or downregulation of the cGAS-STING signaling pathway in the cancer cells within the tumor. mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract Video Abstract video file.(107M, mp4) Supplementary Information The online version contains supplementary material available at 10.1186\/s12964-023-01062-y. Keywords: 4T1 model, 66cl4, 67NR, IFN-I, Metastasis Background The interaction between cancer cells and the tumor microenvironment (TME) profoundly impacts tumor development by influencing processes that lead to either tumor eradication or tumor progression and metastasis [1C4]. In a solid tumor, the transformed cancer cells co-evolve with the TME, which includes fibroblasts, endothelial cells and infiltrating immune cells, blood vessels, signaling molecules, secreted factors, and extracellular matrix [5]. Immune cells are essential components of the TME since a proper antitumor immune response will destroy the transformed cancer cells, while a protumor immune response may support tumor growth and metastasis. Cancer cells can avoid immune recognition by actively suppressing antitumor immune responses by releasing anti-inflammatory cytokines, recruiting immunosuppressive immune cells, and shaping the TME towards a more permissive state [6C14]. Interferons (IFNs) have a crucial role in the immune response against infections, intracellular pathogens, and cancer cells. These proteins are released by infected or transformed cells and activate the immune response that promotes cytokine production, natural killer cell Cadherin Peptide, avian functions, and antigen presentation [15, 16]. Type I IFNs (IFN-I), the largest class of IFNs, have a pivotal role in cancer prevention, inducing anti-tumor immunity [17]. Downregulation of IFN-I response prevents CD8+T cell-mediated recognition and elimination of tumor cells. For instance, loss of the type I interferon receptor chain (IFNAR1) in colorectal cancer models led to aggressive cancer growth, while the activation of IFN-I response increases the CD8+T cell effector function and tumor regression [10, 17, 18]. In breast cancer models, downregulation of interferon Cadherin Peptide, avian regulatory factor (Irf7) target genes was associated with increased bone metastasis and reduced survival in this model. On the other hand, high expression of Irf7 regulatory genes correlated with increased metastasis-free survival in more than 800 patients studied [19]. IFN-I expression can be induced by activating the Cadherin Peptide, avian<\/a> cGAS-STING pathway, which induced tumor regression in breast, colon cancer and melanoma mouse models when STING agonists were administered [20C24]. Moreover, STING agonists are ENDOG<\/a> currently used in clinical trials in combination with chemotherapy or Programmed Cell Death Ligand 1 (PDL1) antibodies highlighting the importance of IFN in cancer treatment [25]. However, a better understanding of the mechanism that controls IFN-I responses and its relationship in the TME components is needed to extend the success of this combined therapy. Despite our improved understanding of anticancer immune responses in the TME, it is still unclear how immuno-suppressive TME are.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffLikely, this downregulation is either due to stimulated removal of DNA from the cytosol or downregulation of the cGAS-STING signaling pathway in the cancer cells within the tumor. mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract Video Abstract video file.(107M, mp4) Supplementary Information The online version contains supplementary material available at 10.1186\/s12964-023-01062-y. Keywords: 4T1 model, 66cl4, 67NR, IFN-I, Metastasis Background The interaction between cancer cells and the tumor microenvironment (TME) profoundly impacts tumor development by influencing processes that lead to either tumor eradication or tumor progression and metastasis [1C4]. In a solid tumor, the transformed cancer cells co-evolve with the TME, which includes fibroblasts, endothelial cells and infiltrating immune cells, blood vessels, signaling molecules, secreted factors, and extracellular matrix [5]. Immune cells are essential components of the TME since a proper antitumor immune response will destroy the transformed cancer cells, while a protumor immune response may support tumor growth and metastasis. Cancer cells can avoid immune recognition by actively suppressing antitumor immune responses by releasing anti-inflammatory cytokines, recruiting immunosuppressive immune cells, and shaping the TME towards a more permissive state [6C14]. Interferons (IFNs) have a crucial role in the immune response against infections, intracellular pathogens, and cancer cells. These proteins are released by infected or transformed cells and activate the immune response that promotes cytokine production, natural killer cell Cadherin Peptide, avian functions, and antigen presentation [15, 16]. Type I IFNs (IFN-I), the largest class of IFNs, have a pivotal role in cancer prevention, inducing anti-tumor immunity [17]. Downregulation of IFN-I response prevents CD8+T cell-mediated recognition and elimination of tumor cells. For instance, loss of the type I interferon receptor chain (IFNAR1) in colorectal cancer models led to aggressive cancer growth, while the activation of IFN-I response increases the CD8+T cell effector function and tumor regression [10, 17, 18]. In breast cancer models, downregulation of interferon Cadherin Peptide, avian regulatory factor (Irf7) target genes was associated with increased bone metastasis and reduced survival in this model. On the other hand, high expression of Irf7 regulatory genes correlated with increased metastasis-free survival in more than 800 patients studied [19]. IFN-I expression can be induced by activating the Cadherin Peptide, avian cGAS-STING pathway, which induced tumor regression in breast, colon cancer and melanoma mouse models when STING agonists were administered [20C24]. Moreover, STING agonists are ENDOG currently used in clinical trials in combination with chemotherapy or Programmed Cell Death Ligand 1 (PDL1) antibodies highlighting the importance of IFN in cancer treatment [25]. However, a better understanding of the mechanism that controls IFN-I responses and its relationship in the TME components is needed to extend the success of this combined therapy. Despite our improved understanding of anticancer immune responses in the TME, it is still unclear how immuno-suppressive TME are.<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[9],"tags":[],"class_list":["post-823","post","type-post","status-publish","format-standard","hentry","category-ppar"],"_links":{"self":[{"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/posts\/823","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/socmexfito.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=823"}],"version-history":[{"count":1,"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/posts\/823\/revisions"}],"predecessor-version":[{"id":824,"href":"https:\/\/socmexfito.org\/index.php?rest_route=\/wp\/v2\/posts\/823\/revisions\/824"}],"wp:attachment":[{"href":"https:\/\/socmexfito.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=823"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/socmexfito.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=823"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/socmexfito.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=823"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}