Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth

Xiao, Yang; Zhang, Yin; Yang, Yunlong; Lim, Sharon; Cao, Ziquan; Rak, Janusz; Cao, Yihai

doi:10.1073/pnas.1309629110

Cited by 61 publications

(45 citation statements)

References 40 publications

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“…To eliminate the host cell-derived VEGF-A from participating in VEGF-B-induced metastasis, we took a pharmacological approach to inhibit VEGF-A in mice bearing murine fibrosarcoma tumors. As expected, treatment of mice bearing vector-T241 tumors with an anti-mouse VEGF-A neutralizing antibody (VEGF-A blockade) (27)(28)(29) resulted in normalized vasculature (Fig. 5A).…”

Section: Anti-vegf-a Treatment Did Not Block Vegf-b-induced Cancer Mesupporting

confidence: 80%

VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

Xiao

Zhang

Hosaka

et al. 2015

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

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125

104

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The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A–null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk−/− mice and mice treated with anti–VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

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Section: Anti-vegf-a Treatment Did Not Block Vegf-b-induced Cancer Mesupporting

confidence: 80%

VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

Xiao

Zhang

Hosaka

et al. 2015

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

Self Cite

125

104

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“…At this time, We confirmed the formation of VEGF, PlGF homodimer, and VEGF/PlGF heterodimer through ELISA in transgenic mice placenta. 21 The result showed that there were no significant differences in the formation of heterodimer between WT and transgenic mice. Instead of it, PlGF homodimer formation was significantly induced because increased levels of PlGF homodimerization may cause placenta detachment ( Figure 5C).…”

Section: Regulation Of Angiogenic Signal In Placentamentioning

confidence: 94%

Gestational Loss and Growth Restriction by Angiogenic Defects in Placental Growth Factor Transgenic Mice

Kang

Park

Kim

et al. 2014

ATVB

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Objective-Angiogenesis is an important biological process during development, reproduction, and in immune responses.Placental growth factor (PlGF) is a member of vascular endothelial growth factor that is critical for angiogenesis and vasculogenesis. We generated transgenic mice overexpressing PlGF in specifically T cells using the human CD2-promoter to investigate the effects of PlGF overexpression. Approach and Results-Transgenic mice were difficult to obtain owing to high lethality; for this reason, we investigated why gestational loss occurred in these transgenic mice. Here, we report that placenta detachment and inhibition of angiogenesis occurred in PlGF transgenic mice during the gestational period. Moreover, even when transgenic mice were born, their growth was restricted. Conclusions-Conclusively, PlGF overexpression prevents angiogenesis by inhibiting Braf, extracellular signal-regulated kinase activation, and downregulation of HIF-1α in the mouse placenta. Furthermore, it affected regulatory T cells, which are important for maintenance of pregnancy. (Arterioscler Thromb Vasc Biol. 2014;34:2276-2282.)

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“…Exosomes derived from several types of cancer cells deliver EGFR to ECs and induce angiogenesis through VEGF/VEGFR2 signaling (120). 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).…”

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

168

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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Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth

Cited by 61 publications

References 40 publications

VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

Gestational Loss and Growth Restriction by Angiogenic Defects in Placental Growth Factor Transgenic Mice

The Multiple Roles of Exosomes in Metastasis

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