Scientists identify protein that promotes brain metastasis
Re: Scientists identify protein that promotes brain metastasis
Scientists identify protein that promotes brain metastasis
Date:
November 4, 2019
Source:
Weill Cornell Medicine
Summary:
A protein that breast, lung and other cancers use to promote their spread -- or metastasis -- to the brain, has been identified. The protein, CEMIP, will now be a focus of efforts to predict, prevent and treat brain metastases, which are a frequent cause of cancer deaths.
Debbie
Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis
CEMIP
Abstract
The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
https://www.nature.com/articles/s41556-019-0404-4
Abstract
The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
https://www.nature.com/articles/s41556-019-0404-4
Debbie
Exosome Traceability and Cell Source Dependence on Composition and Cell-Cell Cross Talk
Exosome Traceability and Cell Source Dependence on Composition and Cell-Cell Cross Talk
Abstract: Exosomes are small vesicles with an average diameter of 100 nm that are produced by many, if not all, cell types. Exosome cargo includes lipids, proteins, and nucleic acids arranged specifically in the endosomes of donor cells. Exosomes can transfer the donor cell components to target cells and can affect cell signaling, proliferation, and differentiation. Important new information about exosomes’ remote communication with other cells is rapidly being accumulated. Recent data indicates that the results of this communication depend on the donor cell type and the environment of the host cell. In the field of cancer research, major questions remain, such as whether tumor cell exosomes are equally taken up by cancer cells and normal cells and whether exosomes secreted by normal cells are specifically taken up by other normal cells or also tumor cells. Furthermore, we do not know how exosome uptake is made selective, how we can trace exosome uptake selectivity, or what the most appropriate methods are to study exosome uptake and selectivity. This review will explain the effect of exosome source and the impact of the donor cell growth environment on tumor and normal cell interaction and communication. The review will also summarize the methods that have been used to label and trace exosomes to date.
Keywords: exosomes; tumor cell-derived exosomes; normal cell-derived exosomes; nanoparticle (NPs); liquid biopsy
https://res.mdpi.com/d_attachment/ijms/ ... 346-v2.pdf
Abstract: Exosomes are small vesicles with an average diameter of 100 nm that are produced by many, if not all, cell types. Exosome cargo includes lipids, proteins, and nucleic acids arranged specifically in the endosomes of donor cells. Exosomes can transfer the donor cell components to target cells and can affect cell signaling, proliferation, and differentiation. Important new information about exosomes’ remote communication with other cells is rapidly being accumulated. Recent data indicates that the results of this communication depend on the donor cell type and the environment of the host cell. In the field of cancer research, major questions remain, such as whether tumor cell exosomes are equally taken up by cancer cells and normal cells and whether exosomes secreted by normal cells are specifically taken up by other normal cells or also tumor cells. Furthermore, we do not know how exosome uptake is made selective, how we can trace exosome uptake selectivity, or what the most appropriate methods are to study exosome uptake and selectivity. This review will explain the effect of exosome source and the impact of the donor cell growth environment on tumor and normal cell interaction and communication. The review will also summarize the methods that have been used to label and trace exosomes to date.
Keywords: exosomes; tumor cell-derived exosomes; normal cell-derived exosomes; nanoparticle (NPs); liquid biopsy
https://res.mdpi.com/d_attachment/ijms/ ... 346-v2.pdf
Debbie
The role of CEMIP in tumors: An update based on cellular and molecular insights
The role of CEMIP in tumors: An update based on cellular and molecular insights
Abstract
CEMIP was initially identified as an inner-ear specific protein in which three-point mutations cause folding changes in protein structure associated with non-syndromic hearing loss. CEMIP was also involved in other cellular activities, such as hyaluronan depolymerization independent of CD44 and other hyaluronidases. Growing evidence has demonstrated that CEMIP is involved in the progression of various tumors. However, whether the oncogenic effects of CEMIP relies on its enzymatic activity remain elusive. CEMIP is significantly related to metastasis and poor prognosis in patients with various tumors, suggesting that CEMIP is a potential, highly specific diagnostic tumor marker. Most preclinical experiments have shown that the overexpression of CEMIP in tumors mainly affects the adhesion, metastasis, and invasion of tumor cells and EMT. Other studies have also demonstrated that CEMIP can promote a variety of tumor processes by affecting tumor proliferation, dedifferentiation, and the tumor microenvironment. In terms of molecular mechanisms, existing research has shown that CEMIP mainly affects the WNT and EGFR signaling pathways. In addition, a variety of miRNAs have been shown to inhibit CEMIP in tumors. This paper elaborates on the clinical characteristics and regulatory dysfunction of CEMIP in different cancers. CEMIP provides a new potential target for therapy of multiple tumors, which is worthy of further study.
https://www.sciencedirect.com/science/a ... 2221012907
Abstract
CEMIP was initially identified as an inner-ear specific protein in which three-point mutations cause folding changes in protein structure associated with non-syndromic hearing loss. CEMIP was also involved in other cellular activities, such as hyaluronan depolymerization independent of CD44 and other hyaluronidases. Growing evidence has demonstrated that CEMIP is involved in the progression of various tumors. However, whether the oncogenic effects of CEMIP relies on its enzymatic activity remain elusive. CEMIP is significantly related to metastasis and poor prognosis in patients with various tumors, suggesting that CEMIP is a potential, highly specific diagnostic tumor marker. Most preclinical experiments have shown that the overexpression of CEMIP in tumors mainly affects the adhesion, metastasis, and invasion of tumor cells and EMT. Other studies have also demonstrated that CEMIP can promote a variety of tumor processes by affecting tumor proliferation, dedifferentiation, and the tumor microenvironment. In terms of molecular mechanisms, existing research has shown that CEMIP mainly affects the WNT and EGFR signaling pathways. In addition, a variety of miRNAs have been shown to inhibit CEMIP in tumors. This paper elaborates on the clinical characteristics and regulatory dysfunction of CEMIP in different cancers. CEMIP provides a new potential target for therapy of multiple tumors, which is worthy of further study.
https://www.sciencedirect.com/science/a ... 2221012907
Debbie
The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets
The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic
Abstract
Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.
Keywords: sarcoma, metastasis, exosome, diagnostic biomarker, therapeutic target
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10046038/
Abstract
Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.
Keywords: sarcoma, metastasis, exosome, diagnostic biomarker, therapeutic target
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10046038/
Last edited by D.ap on Sun Mar 24, 2024 5:45 pm, edited 1 time in total.
Debbie
Re: Scientists identify protein that promotes brain metastasis
“Even when we deleted the CEMIP gene from the cancer cells, providing CEMIP through exosomes restored the molecular environment in brain tissue that allowed the cancer cells to colonize that tissue," said first author Gonçalo Rodrigues, a Ph.D. student co-mentored by Dr. Lyden and Dr. Maria de Sousa, emerita professor at the University of Porto in Portugal and adjunct professor of pediatrics at Weill Cornell Medicine.”
The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic -cont..
2.2. Exosome and PMN Formation in Sarcoma Metastasis
The PMN is a preformed microenvironment made by exosomes secreted by the primary tumor site before widespread metastasis [52,53]. Exosomes optimize the environment for sarcoma colonization, outgrowth, and metastasis [54]. Sarcoma metastasis is a multistep and complex biological process [55]. It is becoming clear that metastasis is not solely a consequence of autonomous sarcoma cell properties, but also a complex interplay between tumor cells and the many components of the metastatic microenvironment, including the extracellular matrix, inflammatory cells, and stimulatory molecules [56]. It is now well established that primary sarcoma cells release exosomes that promote the preparation at future metastatic sites prior to circulating sarcoma cell colonization and thereby favor the establishment of specialized microenvironments, designated as the PMN [42,57]. The formation of PMN in sarcoma is a prevalent precondition of metastasis [40,48].
In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10046038/
Debbie