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1.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34638621

RESUMEN

Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/farmacología , Metaloproteinasa 2 de la Matriz/sangre , Microambiente Tumoral/efectos de los fármacos , Animales , Membrana Basal/efectos de los fármacos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Integrina beta1/metabolismo , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Noqueados , Dominios Proteicos , Microambiente Tumoral/fisiología
2.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34298975

RESUMEN

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.


Asunto(s)
Factor de Transcripción Activador 3/fisiología , Ciclofosfamida/toxicidad , Neoplasias Pulmonares/secundario , Macrófagos/fisiología , Neoplasias Mamarias Experimentales/genética , Metástasis de la Neoplasia/fisiopatología , Proteínas de Neoplasias/fisiología , Estrés Fisiológico/genética , Macrófagos Asociados a Tumores/fisiología , Animales , Péptidos Catiónicos Antimicrobianos/biosíntesis , Péptidos Catiónicos Antimicrobianos/genética , Línea Celular Tumoral , Ciclofosfamida/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Genotipo , Humanos , Neoplasias Pulmonares/metabolismo , Activación de Macrófagos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Ratones Transgénicos , Terapia Neoadyuvante/efectos adversos , Metástasis de la Neoplasia/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Trasplante de Neoplasias/métodos , Células Madre Neoplásicas/patología , Migración Transendotelial y Transepitelial , Microambiente Tumoral , Macrófagos Asociados a Tumores/efectos de los fármacos , Catelicidinas
3.
Proc Natl Acad Sci U S A ; 114(34): E7159-E7168, 2017 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-28784776

RESUMEN

Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive; these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agent-a stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.


Asunto(s)
Factor de Transcripción Activador 3/metabolismo , Antineoplásicos/efectos adversos , Neoplasias de la Mama/metabolismo , Paclitaxel/efectos adversos , Factor de Transcripción Activador 3/genética , Animales , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/fisiopatología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Estrés Fisiológico/efectos de los fármacos
4.
Int J Mol Sci ; 19(11)2018 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-30373101

RESUMEN

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Mama/efectos de los fármacos , Mama/patología , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Metástasis de la Neoplasia/patología , Microambiente Tumoral/efectos de los fármacos
5.
Nat Commun ; 13(1): 6623, 2022 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-36333297

RESUMEN

Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.


Asunto(s)
Reactividad Cruzada , Neoplasias Pulmonares , Ratones , Humanos , Animales , Antígenos de Neoplasias , Linfocitos T CD8-positivos , Células Dendríticas , Neoplasias Pulmonares/metabolismo , Lisosomas , Ratones Endogámicos C57BL , Microambiente Tumoral
6.
Sci Rep ; 7(1): 15441, 2017 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-29133857

RESUMEN

In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-ß in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR-23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKß, AKT2, ERK2 and KRAS itself. Of note, an inverse correlation between miR-23b cluster, miR-125a-5p and respective target genes was also found in vivo in a large dataset of lung adenocarcinoma samples. Furthermore, in vivo delivery of miR-23b cluster or miR-125a-5p significantly repressed tumour growth in a highly aggressive NSCLC circulating tumour cell (CTC) patient derived explant (CDX) mouse model. In conclusion, our finding sheds light on the PDGFR signaling and endorses the possibility to employ miR-23b cluster and miR-125a-5p as therapeutic tools to silence simultaneously a range of redundant pathways and main effectors of tumorigenesis in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/genética , Animales , Antineoplásicos/farmacología , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Terapia Genética , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Ratones , MicroARNs/administración & dosificación , MicroARNs/genética , Persona de Mediana Edad , Familia de Multigenes/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factor de Transcripción ReIA/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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