RESUMEN
Breast cancer is a common malignant tumor arising in normal mammary epithelial tissues. Nearly 75% of the patients with advanced mammary cancer develop bone metastases, resulting in secondary tumor growth, osteolytic bone degradation, and poor prognosis. The bone matrix comprises a highly hierarchical architecture and is composed of a nonmineral organic part, a predominantly type-I collagen, and a mineral inorganic part composed of hydroxyapatite (HA) nanocrystals (Ca10(PO4)6(OH)2). Although there has been extensive research indicating that the material properties of bone minerals affect metastatic breast cancer, it remains unclear how the microenvironment of the bone matrix, such as the roughness, which changes as a result of osteolytic bone remodeling, affects this disease. In this study, we created HA coatings in situ on polyelectrolyte multilayers (PEMs) by incubating PEMs in a mixture of phosphate and calcium ions. The HA films with distinctive roughness were successfully collected by controlling the incubation time, which served as the simulated microenvironment of the bone matrix. MDA-MB231 breast cancer cells were cultured on HA films, and an optimal roughness was observed in the adhesion, proliferation, and expression of two cytokines closely related to bone metastasis. This study contributed to the understanding of the effect of the microenvironment of the bone matrix, such as the roughness, on the metastasis behavior of breast cancer.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Durapatita , Durapatita/química , Humanos , Neoplasias de la Mama/patología , Neoplasias Óseas/secundario , Neoplasias Óseas/patología , Línea Celular Tumoral , Femenino , Microambiente Tumoral/efectos de los fármacos , Propiedades de Superficie , Proliferación Celular/efectos de los fármacos , Adhesión Celular/efectos de los fármacosRESUMEN
Acute lung injury is the leading cause of paraquat (PQ) poisoning-related mortality. The mechanism by which macrophages are involved in PQ-induced acute lung injury remains unclear. In recent years, the role of metabolic reprogramming in macrophage functional transformation has received significant attention. The current study aimed to identify the role of altered macrophage glucose metabolism and molecular mechanisms in PQ poisoning-induced acute lung injury. We established a model of acute lung injury in PQ-intoxicated mice via the intraperitoneal injection of PQ. PQ exposure induces macrophage M1 polarization and promotes the release of inflammatory factors, which causes the development of acute lung injury in mice. In vitro analysis revealed that PQ altered glucose metabolism, which could be reversed by siRNA transfection to silence the expression of HK1, a key enzyme in glucose metabolism. RNA sequencing revealed that the ERK/MAPK pathway was the crucial molecular mechanism of PQ pathogenesis. Further, U0126, an ERK inhibitor, could inhibit PQ-induced HK1 activation and macrophage M1 polarization. These findings provide novel insights into the previously unrecognized mechanism of ERK/MAPK-HK1 activation in PQ poisoning.
Asunto(s)
Lesión Pulmonar Aguda , Glucosa , Hexoquinasa , Sistema de Señalización de MAP Quinasas , Macrófagos , Ratones Endogámicos C57BL , Paraquat , Animales , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Paraquat/toxicidad , Ratones , Glucosa/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Hexoquinasa/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Transducción de Señal/efectos de los fármacos , Células RAW 264.7RESUMEN
The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates. However, chemotherapy in practice has only had limited success in inducing long-term survival or cure of cancers when used either alone or in combination with immunotherapy. We think that this is because the importance of dose, schedule, and tumor model dependence of chemotherapy-activated anti-tumor immunity is under-appreciated. Here, we review immune modulation function of representative chemotherapy agents and propose a model of immunogenic chemotherapy-induced long-lasting responses that rely on synergetic interaction between killing tumor cells and inducing anti-tumor immunity. We comb through several chemotherapy treatment schedules, and identify the needs for chemotherapy dose and schedule optimization and combination therapy with immunotherapy when chemotherapy dosage or immune responsiveness is too low. We further review tumor cell intrinsic factors that affect the optimal chemotherapy dose and schedule. Lastly, we review the biomarkers indicating responsiveness to chemotherapy and/or immunotherapy treatments. A deep understanding of how chemotherapy activates anti-tumor immunity and how to monitor its responsiveness can lead to the development of more effective chemotherapy or chemo-immunotherapy, thereby improving the efficacy of cancer treatment.