Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.
Ontology highlight
ABSTRACT:
SUBMITTER: Gui J
PROVIDER: S-EPMC8194112 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:There is evidence to suggest that the primary tumor induces the formation of a pre-metastatic niche in distal organs by stimulating the production of pro-metastatic factors. Given the fundamental role of the pre-metastatic niche in the development of metastases, interruption of its formation would be a promising strategy to take early action against tumor metastasis. Here we report an enzyme-activated assembled peptide FR17 that can serve as a "flame-retarding blanket" in the pre-metastatic niche specifically to extinguish the "fire" of tumor-supportive microenvironment adaption. We show that the in-situ assembled peptide nano-blanket inhibits fibroblasts activation, suppressing the remodeling of the metastasis-supportive host stromal tissue, and reversing vascular destabilization and angiogenesis. Furthermore, we demonstrate that the nano-blanket prevents the recruitment of myeloid cells to the pre-metastatic niche, regulating the immune-suppressive microenvironment. We show that FR17 administration effectively inhibits the formation of the pulmonary pre-metastatic niche and postoperative metastasis, offering a therapeutic strategy against pre-metastatic niche formation.
| S-EPMC9132894 | biostudies-literature
Project description:Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.
| S-EPMC8316194 | biostudies-literature
Project description:Here we report an enzyme-activatable assembled peptide FR17 that can serve as a “flame-retarding blanket” at pre-metastatic niche (PMN) specifically to extinguish the “fire” of tumor-supportive microenvironment adaption. Our experiment demonstrated that the assembled peptide successfully reversed extracellular matrix deposition, vascular leakage and angiogenesis through inhibition on fibroblasts activation in PMN, which suppressed the remodeling of metastasis-supportive host stromal, and further prevented the recruitment of myeloid cells to PMN and then recovered the immunosuppressive microenvironment. Cell transcriptomic analysis of the pulmonary recruited MDSC suggested that FR17 intervention could regulate immune response activation, immune cells chemotaxis and migration pathways. Consequently, FR17 administration effectively inhibited pulmonary PMN formation and postoperative metastasis of melanoma, with only 30% lung-metastasis occurrence was observed for FR17 treated group at the time point when 100% occurrence was observed for the control group and 80% occurrence for anti-PD1 treated group, offering a robust therapeutic strategy against PMN establishing to prevent metastasis.
2022-02-08 | GSE181898 | GEO
Project description:In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1?, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C-X-C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ's microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future.
| S-EPMC7764404 | biostudies-literature
Project description:Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
| S-EPMC5769922 | biostudies-literature
Project description:The disordered growth, invasion and metastasis of cancer are mainly attributed to bidirectional cell-cell interactions. Extracellular vesicles (EVs) secreted by cancer cells are involved in orchestrating the formation of pre-metastatic niches (PMNs). Tumor-derived EVs mediate bidirectional communication between tumor and stromal cells in local and distant microenvironments. EVs carrying mRNAs, small RNAs, microRNAs, DNA fragments, proteins and metabolites determine metastatic organotropism, enhance angiogenesis, modulate stroma cell phenotypes, restructure the extracellular matrix, induce immunosuppression and modify the metabolic environment of organs. Evidence indicates that EVs educate stromal cells in secondary sites to establish metastasis-supportive microenvironments for seeding tumor cells. In this review, we provide a comprehensive overview of PMN formation and the underlying mechanisms mediated by EVs. Potential approaches to inhibit cancer metastasis by inhibiting the formation of PMNs are also presented.
| S-EPMC10940351 | biostudies-literature
Project description:A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.
| S-EPMC5724390 | biostudies-literature
Project description:Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A+ TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1+) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1+ myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1+ myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1+ myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.
| S-EPMC5582214 | biostudies-literature
Project description:The pre-metastatic niche - the accumulation of aberrant immune cells and extracellular matrix proteins in target organs - primes the initially healthy organ microenvironment and renders it amenable for subsequent metastatic cell colonization. By attracting metastatic cancer cells, mimics of the pre-metastatic niche offer both diagnostic and therapeutic potential. However, deconstructing the complexity of the niche by identifying the interactions between cell populations and the mediatory roles of the immune system, soluble factors, extracellular matrix proteins, and stromal cells has proved challenging. Experimental models need to recapitulate niche-population biology in situ and mediate in vivo tumour-cell homing, colonization and proliferation. In this Review, we outline the biology of the pre-metastatic niche and discuss advances in engineered niche-mimicking biomaterials that regulate the behaviour of tumour cells at an implant site. Such oncomaterials offer strategies for early detection of metastatic events, inhibiting the formation of the pre-metastatic niche, and attenuating metastatic progression.
| S-EPMC5628747 | biostudies-literature
Project description:Exosomes play important roles in cell-cell communication, and are likely mediators of the metastatic cascade in cancer. This study examined the role of exosomes in pancreatic cancer cell adhesion, migration, and invasion. We isolated and purified exosomes from two isogenic pancreatic cancer cell lines with different metastatic potentials. Uptake of exosomes from highly metastatic Panc02-H7 cells decreased adhesion and increased migration and invasion capacity in weakly metastatic Panc02 cells in vitro. Exosomes from highly metastatic pancreatic cancer cells induced liver pre-metastatic niche formation in naïve mice and promoted primary tumor growth and liver metastasis in vivo. We identified 4,517 proteins in exosomes from Panc02 and Panc02-H7 cells via iTRAQ quantitative proteomic analyses, 79 of which were differentially expressed between the two cell lines. Bioinformatics analyses showed that most of the differentially expressed proteins were involved in pancreatic cancer growth, invasion, and metastasis, and that metabolism-related signaling pathways were involved in exosome-mediated intracellular communication. Further studies will be needed to determine whether these proteins are potential pancreatic cancer diagnostic/prognostic markers or novel therapeutic targets.
| S-EPMC5609937 | biostudies-literature