Fibronectin Distribution in Human Bone Marrow Stroma: Matrix Assembly and Tumor Cell Adhesion via α5β1 Integrin

Velde-Zimmermann, Detlef van der; Verdaasdonk, M.A.M.; Rademakers, L. H. P. M.; Weger, R. A. De; Tweel, Jan G. van den; Joling, Piet

doi:10.1006/excr.1996.3405

Cited by 50 publications

(40 citation statements)

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“…Fibronectin is abundantly expressed in the bone marrow microenvironment by stromal cells. 18 In studies of adhesion-molecule profiles of disseminated tumor cells recovered from bone marrow aspirates of patients with bone metastases, the a5b1 integrin was expressed in nearly 100% of disseminated tumor cells. 19 Interestingly, the alternate FN receptor a4b1 (VLA-4) has been implicated in the homing of haematopoietic stem cells to the marrow-niche; neutralizing antibodies to a4b1 mobilize haematopoietic stem cells into circulation implicating FN as a functional component of the haematopoietic niche.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Joshi

Goihberg

Ren

et al. 2016

Cell Adhesion & Migration

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The haematopoietic niche is contributed to by bone marrow-resident mesenchymal stromal cells (BM-MSCs) and subverted by prostate cancer cells. To study mechanisms by which BM-MSCs and prostate cancer cells may interact, we assessed the migration, invasion, adhesion and proliferation of bone-derived prostate cancer cells (PC-3) in co-culture with pluripotent human BM-MSCs. We observed a strong adhesive, migratory and invasive phenotype of PC-3 cells with BM-MSC-coculture and set out to isolate and characterize the bioactive principle. Initial studies indicated that chemotaxis was secondary to a protein residing in the >100kDa fraction. Size-exclusion chromatography (SEC) recovered peak activity in a high-molecular weight fraction containing thrombospondin-1 (TSP1). While TSP1 immunodepletion decreased activity, put-back with purified TSP1 did not reproduce bioactivity. Further purification of the TSP1-containing high-molecular weight fraction of the BM-MSC secretome with heparin-affinity chromatography recovered bioactivity with highly restricted bands on polyacrylamide gel electrophoresis, determined by mass spectroscopy to be proteolytic fragments of fibronectin (FN). Put-back experiments with full-length FN permitted adhesion but failed to induce migration. Monospecific antibodies to FN blocked adhesion. Proteolytic cleavage of FN generated FN fragments which now induced migration. Neutralizing monoclonal antibodies to FN receptors a5 and b1 integrins, and a5 knockdown specifically blocked migration and adhesion. Conclusion: Fibronectin fragments (FNFr) function as matrikines driving the chemotactic affinity of prostate cancer cells via the a5b1 integrin. Taken together with the high-frequency of a5b1 expression in disseminated prostate cancer cells in bone marrow aspirates from patients, the FNFr/FN-a5b1 interaction warrants further study as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Joshi

Goihberg

Ren

et al. 2016

Cell Adhesion & Migration

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“…31 Blocking α5β1 integrins by monoclonal antibodies inhibits adhesion of DU-145 PCa cell to bone marrow stromal cells. 31, 32 Another β1 integrin family protein, α2β1, has been shown to increase migration and adhesion of collagen-binding LNCaP cells on collagen I, and promotes bone metastasis in vivo . 33, 34 Similar to α5β1, α2β1 was found to mediate adhesion of malignant tumor-derived prostate epithelial cells to human bone marrow stroma, which can also be inhibited by antibodies targeting α2β1.…”

Section: Discussionmentioning

confidence: 99%

Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

et al. 2014

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Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We previously showed that β1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how β1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of β1 integrin activation. Using knockdown experiments, we first demonstrated talin1, but not talin2, is important in β1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of β1 integrins, integrin-mediated adhesion, motility, and increased the sensitivity of the cells to anoikis. In contrast, re-expression of the phosphorylation-mimicking mutant talin1S425D led to increased β1 integrin activation and generated biologic effects opposite to talin1S425A expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while re-expression of phosphorylation-mimicking mutant talin1S425D restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared to normal tissues, primary tumors, or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent β1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to β1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells.

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“…In vitro confocal laser microscope analysis showed that hMSCs produce high amounts of fibronectin, especially at contact points between cells. By using α5β1 integrin- and fibronectin-blocking anti-bodies, it was clarified that the tested tumour cell lines were not able to adhere on hMSCs [96]. Last to be discussed is an article where a mechanism for the metastasis of primary prostatic epithelial cells has been investigated.…”

Section: Engagement Of Integrins In Hmsc Differentiation Attachment mentioning

confidence: 99%

Human mesenchymal stem cells in contact with their environment: surface characteristics and the integrin system

Docheva

Popov

Mutschler

et al. 2007

J Cellular Molecular Medi

279

172

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The identification of mesenchymal stem cells (MSCs) in adult human tissues and the disclosure of their self-renew-al and multi-lineage differentiation capabilities have provided exciting prospects for cell-based regeneration and tis-sue engineering. Although a considerable amount of data is available describing MSCs, there is still lack of information regarding the molecular mechanisms that govern their adhesion and migration. In this work, we will review the current state of knowledge on integrins and other adhesion molecules found to be expressed on MSCs. The dis-cussed topics include the characteristics of MSCs and their clinical applications, integrins and their central role in cell-matrix attachment and migration, and comments on mobilization, differentiation and contribution to tumour development. Finally, by understanding the complex and fundamental pathways by which MSCs attach and migrate, it might be possible to fine-tune the strategies for effective and safe use of MSCs in regenerative therapies.

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Fibronectin Distribution in Human Bone Marrow Stroma: Matrix Assembly and Tumor Cell Adhesion via α5β1 Integrin

Cited by 50 publications

References 0 publications

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

Human mesenchymal stem cells in contact with their environment: surface characteristics and the integrin system

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