Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Svensson, Katrin J.; Kucharzewska, Paulina; Christianson, Helena C.; Sköld, Stefan; Löfstedt, Tobias; Johansson, Martin; Mörgelin, Matthias; Bengzon, Johan; Ruf, Wolfram; Belting, Mattias

doi:10.1073/pnas.1104261108

Cited by 260 publications

(219 citation statements)

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“…In addition to TF, hypoxic stress has been shown to modulate PAR1 expression in tumor cell lines (32,33). Furthermore, our recent study observed increased PAR1 and PAR2 staining around necrotic areas in samples from patients with GBM (22).…”

Section: Hypoxic Induction Of Par Expression In P7 and St1 Cellsmentioning

confidence: 95%

“…No significant FXa generation was observed in the absence of FVIIa. Hypoxia has been shown to markedly increase TF-containing extracellular vesicle secretion in glioma cells (32). Therefore, the present study investigated whether hypoxia increases the secretion of MVs into the conditioned media of P7 and ST1 cell cultures.…”

Section: Shedding Of Procoagulant Mvs By P7 and St1 Cells Tf Has Beenmentioning

confidence: 99%

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Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

et al. 2016

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Abstract. Hypoxia and necrosis are fundamental features of glioma, and their emergence is critical for the rapid biological progression of this fatal tumor. The presence of vaso-occlusive thrombus is higher in grade IV tumors [glioblastoma multiforme (GBM)] compared with lower grade tumors, suggesting that the procoagulant properties of the tumor contribute to its aggressive behavior, as well as the establishment of tumor hypoxia and necrosis. Tissue factor (TF), the primary cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Phosphatase and tensin homolog (PTEN) loss and hypoxia are two common alterations observed in glioma that may be responsible for TF upregulation. In the present study, ST1 and P7 rat glioma lines, with different levels of aggressiveness, were comparatively analyzed with the aim of identifying differences in procoagulant mechanisms. The results indicated that P7 cells display potent procoagulant activity compared with ST1 cells. Flow cytometric analysis showed less pronounced levels of TF in ST1 cells compared with P7 cells. Notably, P7 cells supported factor X (FX) activation via factor VIIa, whereas no significant FXa generation was observed in ST1 cells. Furthermore, the exposure of phosphatidylserine on the surface of P7 and ST1 cells was investigated. The results supported the assembly of prothrombinase complexes, accounting for the production of thrombin. Furthermore, reverse transcription-quantitative polymerase chain reaction showed that CoCl 2 (known to induce a hypoxic-like stress) led to an upregulation of TF levels in P7 and ST1 cells. Therefore, increased TF expression in P7 cells was accompanied by increased TF procoagulant activity. In addition, hypoxia increased the shedding of procoagulant TF-bearing microvesicles in both cell lines. Finally, hypoxic stress induced by treatment with CoCl 2 upregulated the expression of the PAR1 receptor in both P7 and ST1 cells. In addition to PAR1, P7, but not ST1 cells, expressed higher levels of PAR2 under hypoxic stress. Thus, modulating these molecular interactions may provide additional insights for the development of more efficient therapeutic strategies against aggressive glioma.

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Section: Hypoxic Induction Of Par Expression In P7 and St1 Cellsmentioning

confidence: 95%

Section: Shedding Of Procoagulant Mvs By P7 and St1 Cells Tf Has Beenmentioning

confidence: 99%

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

et al. 2016

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“…Glioblastoma cells grown under hypoxic conditions were shown to produce exosomes that deliver pro-angiogenic factors such as IL8 and PDGF to ECs (121). An additional example is the transfer of tissue factor by tumor-cell derived exosomes to ECs, resulting in activation of GPCR proteaseactivated receptor 2 and subsequent upregulation of HB-EGF, promoting an angiogenic EC phenotype (122). Promotion of brain metastasis by breast cancer cell-derived exosomal miRs after transfer to ECs was documented in two reports (115,123).…”

Section: Metastasis-related Interactions Between Cancer Cell-derived mentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

163

128

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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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“…Hypoxia has been reported to induce increased release of proangiogenic extracellular vesicles (6,(39)(40)(41). Hypoxia-induced…”

mentioning

confidence: 99%

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang

Gilkes²,

Takano³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

384

363

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Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxiainducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.orthotopic transplantation | triple negative breast cancer | oxygen | tumor microenvironment | mammary fat pad implantation

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Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Cited by 260 publications

References 35 publications

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

The Multiple Roles of Exosomes in Metastasis

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

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