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Molekuliarnaia Biologiia 2018Laminins are a family of extracellular heterotrimeric glycoproteins that are the main structural component of basement membranes (BMs), perform a barrier function, and... (Review)
Review
Laminins are a family of extracellular heterotrimeric glycoproteins that are the main structural component of basement membranes (BMs), perform a barrier function, and are important for adhesion, differentiation, migration, and resistance to apoptosis of various cells, including cancer cells. The review summarizes the current knowledge of how laminins produced by cancer and normal cells influence the key stages of carcinogenesis. Laminin 332 (LN-332) and LN-111 enhance proliferation of certain cancer cells and increase the tumour growth. LN-111 increases resistance to apoptosis, induces differentiation, and inhibits the epithelial-mesenchymal transition (EMT) of cancer cells. LN-332 is associated with higher adhesion and higher migration potential of cancer cells. LN-411 and LN-421 significantly increase motility of cancer cells. LN-332 and LN-511 facilitate cell-cell adhesion and affect the efficacy of cell-cell interactions. The laminin chains α4 and α5 are important for the development and function of blood and lymphatic vessels. The expression ratio of the α4 and α5 laminin chains defines the BM permeability to leukocytes and, presumably, cancer cells in blood and lymphatic vessels. Interactions between LN-511 and α2-containing laminins enhance self-renewal and survival of circulating cancer stem cells. Moreover, laminins are involved in the formation of premetastatic niches and new colonies. Endogenous expression of the α4 laminin chain stimulates proliferation of individualised circulating cancer cells in vitro and in vivo and facilitates micrometastasis.
Topics: Animals; Cell Movement; Humans; Laminin; Neoplasm Proteins; Neoplasms; Neoplastic Cells, Circulating
PubMed: 29989574
DOI: 10.7868/S0026898418030059 -
Signal Transduction and Targeted Therapy Aug 2022Hepatic progenitor cells (HPCs) hold tremendous potential for liver regeneration, but their well-known limitation of proliferation hampers their broader use. There is...
Hepatic progenitor cells (HPCs) hold tremendous potential for liver regeneration, but their well-known limitation of proliferation hampers their broader use. There is evidence that laminin is required for the proliferation of HPCs, but the laminin isoform that plays the dominant role and the key intracellular downstream targets that mediate the regulation of HPC proliferation have yet to be determined. Here we showed that p53 expression increased gradually and reached maximal levels around 8 days when laminin α4, α5, β2, β1, and γ1 subunit levels also reached a maximum during HPC activation and expansion. Laminin-521 (LN-521) promoted greater proliferation of HPCs than do laminin, matrigel or other laminin isoforms. Inactivation of p53 by PFT-α or Ad-p53 inhibited the promotion of proliferation by LN-521. Further complementary MRI and bioluminescence imaging analysis showed that p53 inactivation decreased the proliferation of transplanted HPCs in vivo. p53 was activated by LN-521 through the Integrin α6β1/FAK-Src-Paxillin/Akt axis. Activated p53 was involved in the nuclear translocation of CDK4 and inactivation of Rb by inducing p27. Taken together, this study identifies LN-521 as an ideal candidate substrate for HPC culture and uncovers an unexpected positive role for p53 in regulating proliferation of HPCs, which makes it a potential target for HPC-based regenerative medicine.
Topics: Cell Proliferation; Integrin alpha6beta1; Laminin; Stem Cells; Tumor Suppressor Protein p53
PubMed: 36042225
DOI: 10.1038/s41392-022-01107-7 -
Proceedings of the National Academy of... Nov 2022Organoid technology has provided unique insights into human organ development, function, and diseases. Patient-derived organoids are increasingly used for drug...
Organoid technology has provided unique insights into human organ development, function, and diseases. Patient-derived organoids are increasingly used for drug screening, modeling rare disorders, designing regenerative therapies, and understanding disease pathogenesis. However, the use of Matrigel to grow organoids represents a major challenge in the clinical translation of organoid technology. Matrigel is a poorly defined mixture of extracellular matrix proteins and growth factors extracted from the Engelbreth-Holm-Swarm mouse tumor. The extracellular matrix is a major driver of multiple cellular processes and differs significantly between tissues as well as in healthy and disease states of the same tissue. Therefore, we envisioned that the extracellular matrix derived from a native healthy tissue would be able to support organoid growth akin to organogenesis in vivo. Here, we have developed hydrogels from decellularized human and bovine endometrium. These hydrogels supported the growth of mouse and human endometrial organoids, which was comparable to Matrigel. Organoids grown in endometrial hydrogels were proteomically more similar to the native tissue than those cultured in Matrigel. Proteomic and Raman microspectroscopy analyses showed that the method of decellularization affects the biochemical composition of hydrogels and, subsequently, their ability to support organoid growth. The amount of laminin in hydrogels correlated with the number and shape of organoids. We also demonstrated the utility of endometrial hydrogels in developing solid scaffolds for supporting high-throughput, cell culture-based applications. In summary, endometrial hydrogels overcome a major limitation of organoid technology and greatly expand the applicability of organoids to understand endometrial biology and associated pathologies.
Topics: Female; Humans; Cattle; Animals; Organoids; Hydrogels; Laminin; Proteomics; Endometrium; Neoplasms
PubMed: 36279452
DOI: 10.1073/pnas.2208040119 -
Cancer Science Feb 2006The development and progression of tumor cells is controlled by their interactions with neighboring host cells and a variety of microenvironmental factors including... (Review)
Review
The development and progression of tumor cells is controlled by their interactions with neighboring host cells and a variety of microenvironmental factors including extracellular matrix (ECM) molecules, growth factors and proteinases. Cell-adhesive ECM proteins are a prerequisite for growth and migration of many types of cells. Their interactions with integrins and other cell surface receptors induce intracellular signaling that regulates the actin cytoskeleton and gene expression. The basement membrane protein laminin-5 is a notable cell adhesion molecule, which promotes cellular adhesion and migration much more efficiently than other ECM proteins. There is accumulating evidence that laminin-5 is involved in tumor growth and progression. With special reference to laminin-5, this article reviews the regulatory mechanisms of cellular adhesion and migration by ECM molecules and their significance in tumor progression.
Topics: Humans; Laminin; Neoplasm Invasiveness; Neoplasms
PubMed: 16441418
DOI: 10.1111/j.1349-7006.2006.00150.x -
The International Journal of... Mar 1993The mouse embryonal carcinoma lines PCC4-F and F9 have played important roles in the isolation and characterization of the two ubiquitous basement membrane proteins,... (Review)
Review
The mouse embryonal carcinoma lines PCC4-F and F9 have played important roles in the isolation and characterization of the two ubiquitous basement membrane proteins, laminin and entactin. The contributions of these cells to our work on extracellular matrices are briefly summarized. The in vitro differentiation of PCC4-F gives rise to a multiplicity of cell types. Two of these cell types have been propagated as cell lines. One of these, M1536-B3, synthesizes and deposits copious quantities of extracellular matrix glycoproteins, which led to the initial discovery and characterization of laminin and entactin. In addition, M1536-B3 provides a model system for analyzing the assembly of laminin and the laminin-entactin complex and for manipulating extracellular matrix structure and composition. The other cell line, 4CQ, synthesizes a matrix consisting of fibronectin and entactin. F9 cells differentiate to endodermal cells in response to retinoic acid and dibutyryl cyclic AMP (Strickland and Mahdavi, Cell 15: 393-402, 1978). The differentiated cells synthesize basement membrane components and provided the probes for the cDNA cloning of entactin and the three chains of laminin. The F9 cells have been widely employed to examine the regulation of expression of the laminin and entactin genes.
Topics: Animals; Basement Membrane; Laminin; Membrane Glycoproteins; Mice; Neoplasm Proteins; Teratoma
PubMed: 8507559
DOI: No ID Found -
American Journal of Physiology. Lung... Dec 2019Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway...
Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the α2-chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin α4 and α5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling, and inflammation in asthma. Expression of both laminin α4 and α5 was observed in the human and mouse ASM bundle. In vitro, laminin α4 was found to promote a pro-proliferative, pro-contractile, and pro-fibrotic ASM cell phenotype. In line with this, treatment with laminin α4 and α5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin α4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM α4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin α4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin α4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin α5 is more subtle.
Topics: Adolescent; Adult; Aged; Airway Remodeling; Animals; Asthma; Eosinophils; Female; Humans; Inflammation; Laminin; Male; Mice; Mice, Inbred BALB C; Middle Aged; Muscle Contraction; Young Adult
PubMed: 31553662
DOI: 10.1152/ajplung.00222.2019 -
Cell Adhesion & Migration 2013Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and... (Review)
Review
Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and functions. The laminin-511 heterotrimer (α5β1γ1) is one of the more recent isoforms to be identified and a potent adhesive and pro-migratory substrate for a variety of normal and tumor cell lines in vitro. As our understanding of its precise function in normal tissues and in pathologies is rapidly unraveling, current evidence suggests an important regulatory role in cancer. This review describes published data on laminin-511 expression in several malignancies and experimental evidence from both in vitro and in vivo studies supporting its functional role during tumor progression. A particular emphasis is put on more recent studies from our laboratory and that of others indicating that laminin-511 contributes to tumor dissemination and metastasis in advanced breast carcinomas and other tumor types. Collectively, the experimental evidence suggests that high expression of laminin-511 has prognostic significance and that targeting tumor-laminin-511 interactions may have therapeutic potential in advanced cancer patients.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Integrin alpha6beta1; Laminin; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; Protein Isoforms
PubMed: 23076212
DOI: 10.4161/cam.22125 -
Developmental Biology Jun 2006Laminins are a major component of basement membranes. Each laminin molecule is a heterotrimeric glycoprotein composed of one alpha, one beta, and one gamma chain.... (Review)
Review
Laminins are a major component of basement membranes. Each laminin molecule is a heterotrimeric glycoprotein composed of one alpha, one beta, and one gamma chain. Fifteen laminin isoforms exist, assembled from various combinations of 5alpha, 3beta, and 3gamma chains. The embryonic lung has abundant laminin isoforms. Increasing evidence suggests that different laminin isoforms have unique functions in lung development. Studies of embryonic lung explants and organotypic co-cultures show that laminin alpha1 and laminin 111 are important for epithelial branching morphogenesis and that laminin alpha2 and laminin 211 have a role in smooth muscle cell differentiation. In vivo studies of laminin alpha5-deficient mice indicate that this laminin chain, found in laminins 511 and 521, is essential for normal lobar septation in early lung development and normal alveolization and distal epithelial cell differentiation and maturation in late lung development. However, not all of the laminin chains present in the developing lung appear to be necessary for normal lung development since laminin alpha4 null mice do not have obvious lung abnormalities and laminin gamma2 null mice have only minimal changes in lung development. The mechanisms responsible for the lung phenotypes in mice with laminin mutations are unknown, but it is clear that multiple laminin isoforms are crucial for lung development and that different laminin isoforms exhibit specific, non-overlapping functions.
Topics: Animals; Basement Membrane; Epithelial Cells; Humans; Laminin; Ligands; Lung; Models, Molecular; Protein Isoforms; Protein Subunits
PubMed: 16643883
DOI: 10.1016/j.ydbio.2006.03.032 -
Scientific Reports Dec 2019In the developing central nervous system (CNS), oligodendrocyte precursor cells (OPCs) migrate along blood vessels and are widely distributed in the CNS. Meanwhile, OPCs...
In the developing central nervous system (CNS), oligodendrocyte precursor cells (OPCs) migrate along blood vessels and are widely distributed in the CNS. Meanwhile, OPCs require survival factors from the extracellular microenvironment. In other tissues, laminins, heterotrimetric (αβγ) extracellular matrix proteins, promote cell migration and survival. However, the expression pattern and functions of laminins in OPC development remain poorly understood. In the present study, we first investigated the expression of laminin α chains, which bind to cell surface receptors such as integrins, in the postnatal murine brain. We found that laminin α1, α2, α4, and α5 chains were expressed around blood vessels and OPCs attached the laminin α chain-positive vessels. We then evaluated the effect of these laminins on OPCs activity using recombinant laminin E8s (LME8s) that are minimally active fragments of the laminin isoforms. OPCs attached on LM211E8, LM411E8, and LM511E8, containing laminin α2, α4, and α5 chains, respectively, through integrin β1. Further, these three LME8s promoted migration of OPCs, and OPC survival was prolonged on either LM411E8 or LM511E8 via the activation of focal adhesion kinase. Together, our findings suggest that laminins expressed surrounding blood vessels positively regulate migration and survival of OPCs through the integrin β1-FAK pathway.
Topics: Animals; Cell Adhesion; Cell Movement; Cell Survival; Humans; Laminin; Mice; Mice, Transgenic; Oligodendroglia; Stem Cells
PubMed: 31882770
DOI: 10.1038/s41598-019-56488-7 -
Kidney International Jan 1993Laminin is a member of a family of proteins that are composed of three subunits, one heavy chain and two light chains. Five subunits in the laminin family have been... (Review)
Review
Laminin is a member of a family of proteins that are composed of three subunits, one heavy chain and two light chains. Five subunits in the laminin family have been cloned and sequenced so far. These include two heavy chains, the laminin A chain and the merosin M chain, and three light chains, B1, B2, and S. These five subunits can form four different laminin variants: A-B1-B2, A-S-B2, M-B1-B2, and M-S-B2, all having the B2 chain in common. Major basement membranes in tissues contain at least one of the four laminin variants. For example, the adult muscle and nerve basement membranes contain M-B1-B2, smooth muscle contains A-B1-B2, the myotendinous junction and the trophoblast basement membrane in the placenta contain M-S-B2, and blood vessels contain A-B1-B2 and/or A-S-B2. In the brain, the merosin M chain is present in association with neuronal fibers. The four members of the laminin family interact with cells in a similar manner. Thus, they promote outgrowth of neurites from neuronal cells and promote attachment and spreading of non-neuronal cells. The interaction of cells with laminins is mediated largely by integrin type receptors, including integrins alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1. The expression of the different laminin-like proteins is developmentally regulated. The laminin A chain is the first heavy chain expressed.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Gene Expression; Genetic Variation; Humans; Laminin; Molecular Structure; Nerve Regeneration
PubMed: 8433559
DOI: 10.1038/ki.1993.2