Tumor Cell Cross Talk with Tumor-Associated Leukocytes Leads to Induction of Tumor Exosomal Fibronectin and Promotes Tumor Progression

Deng, Zhongbin; Cheng, Ziqiang; Xiang, Xiaoyu; Yan, Jun; Zhuang, Xiaoying; Liu, Cunren; Jiang, Hong; Ju, Songwen; Zhang, Lifeng; Grizzle, William E.; Mobley, James A.; Roman, Jesse; Miller, Donald R.; Zhang, Huang‐Ge

doi:10.1016/j.ajpath.2011.09.023

Cited by 41 publications

(33 citation statements)

References 35 publications

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“…In this case, it was demonstrated that ϳ50% of the fibronectin could be displaced from exosomes by incubation with the RGD peptide, indicating that at least some of the fibronectin was bound to the exosome via integrins. Similarly, fibronectin was found on the surface of exosomes isolated from ex vivo cultured 4T1 breast cancer cells, and those exosomes could stimulate tumor cell migration via activation of integrins (39). However, none of the above studies examined whether the fibronectin on the exosomes being studied associated with heparan sulfate present either on the exosome or on the cell surface.…”

Section: Discussionmentioning

confidence: 96%

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Purushothaman

Bandari²,

Liu

et al. 2016

Journal of Biological Chemistry

237

225

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Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosomecell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression.

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Section: Discussionmentioning

confidence: 96%

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Purushothaman

Bandari²,

Liu

et al. 2016

Journal of Biological Chemistry

237

225

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“…They have been found to exert immunosuppressive effects by blocking the activity of the host T cells (34). In addition, they seem to play a key role in tumor cell communication within the tumor microenvironment, and are also involved in drug resistance (35,36). Furthermore, tumor-derived exosomes have just been reported to be prometastatic in melanoma (37).…”

Section: Discussionmentioning

confidence: 99%

Unconventional Secretion is a Major Contributor of Cancer Cell Line Secretomes

Villarreal

Méndez

Salvans

et al. 2013

Molecular & Cellular Proteomics

105

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A challenge in achieving optimal management of cancer is the discovery of secreted biomarkers that represent useful surrogates for the disease and could be measured noninvasively. Because of the problems encountered in the proteomic interrogation of plasma, secretomes have been proposed as an alternative source of tumor markers that might be enriched with secreted proteins relevant to the disease. However, secretome analysis faces analytical challenges that interfere with the search for true secreted tumor biomarkers. Here, we have addressed two of the main challenges of secretome analysis in comparative discovery proteomics. First, we carried out a kinetics experiment whereby secretomes and lysates of tumor cells were analyzed to monitor cellular viability during secretome production. Interestingly, the proteomic signal of a group of secreted proteins correlated well with the apoptosis induced by serum starvation and could be used as an internal cell viability marker. We then addressed a second challenge relating to contamination of serum proteins in secretomes caused by the required use of serum for tumor cell culture. The comparative proteomic analysis between cell lines labeled with SILAC showed a number of false positives coming from serum and that several proteins are both in serum and being secreted from tumor cells. A thorough study of secretome methodology revealed that under optimized experimental conditions there is a substantial fraction of proteins secreted through unconventional secretion in secretomes. Finally, we showed that some of the nuclear proteins detected in secretomes change their cellular localization in breast tumors, explaining their presence in secretomes and suggesting that tumor cells use unconventional secretion during tumorigenesis. The unconventional secretion of proteins into the extracellular space exposes a new layer of genome post-translational regulation and reveals an untapped source of potential tumor biomarkers and drug targets. Molecular & Cellular

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“…The alterations, as described, resulted in enhancement of metastases in human breast cancer xenograft models. Another example is enhancement of metastases by TCderived exosomes after co-culturing of 4T1 breast cancer cells with immuno-suppressive leukocytes (128). It was shown that TC-derived exosomes take-up FN and after fusion with other TCs are able to activate production of proinflammatory cytokines and MMP9 as well as FAK signaling, resulting in promotion of metastasis.…”

Section: Metastasis Promotion By Exosomes Based On Immuno-suppressionmentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

167

133

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Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

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Tumor Cell Cross Talk with Tumor-Associated Leukocytes Leads to Induction of Tumor Exosomal Fibronectin and Promotes Tumor Progression

Cited by 41 publications

References 35 publications

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Unconventional Secretion is a Major Contributor of Cancer Cell Line Secretomes

The Multiple Roles of Exosomes in Metastasis

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