Interleukin 7 upregulates vascular endothelial growth factor D in breast cancer cells and induces lymphangiogenesis <i>in vivo</i>

Al-Rawi, Mahir A.; Watkins, Gareth; Mansel, Robert Edward; Jiang, Wen Guo

doi:10.1002/bjs.4832

Cited by 43 publications

(30 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our finding that partial loss of Sox18 function compromises tumor lymphatic vessel density and diameter suggests that SOX18 might be also involved in the modulation of the response by the lymphatic endothelium to VEGF-D/VEGF-C or interleukin signals (37,39). These observations contrast with our previous analysis of the nonpathologic lymphatic vasculature that revealed higher vessel density ( Supplementary Fig.…”

Section: Sox18 and Vegf: Independent Pathways Or Downstream Signaling?contrasting

confidence: 89%

“…During tumorigenesis, a combination of growth factors and cytokines secreted by the tumor and the host tissue triggers remodeling of the preexisting lymphatic vascular network that will further expand, increasing in vessel density but also in vessel diameter (9,37,38). Our finding that partial loss of Sox18 function compromises tumor lymphatic vessel density and diameter suggests that SOX18 might be also involved in the modulation of the response by the lymphatic endothelium to VEGF-D/VEGF-C or interleukin signals (37,39).…”

Section: Sox18 and Vegf: Independent Pathways Or Downstream Signaling?mentioning

confidence: 85%

See 1 more Smart Citation

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

et al. 2012

View full text Add to dashboard Cite

The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade. Cancer Res; 72(12);

show abstract

Section: Sox18 and Vegf: Independent Pathways Or Downstream Signaling?contrasting

confidence: 89%

Section: Sox18 and Vegf: Independent Pathways Or Downstream Signaling?mentioning

confidence: 85%

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Notably, IL-7 had been previously linked with tumor lymphangiogenesis and thought to act indirectly by upregulating VEGF-D in IL-7R-expressing tumor cells. 43,44 In light of our new in vivo findings, it is likely that IL-7 also displays direct lymphangiogenic activity on LECs in vivo, but we presently cannot exclude any indirect contribution from IL-7 responsive hematopoietic cells, such as T cells or LTi cells.…”

Section: Discussionmentioning

confidence: 90%

Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage

Iolyeva

Aebischer

Proulx

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• Afferent lymphatic vessels express interleukin-7.• Interleukin-7 supports lymphatic drainage.The cytokine interleukin (IL)-7 exerts essential roles in lymph node (LN) organogenesis and lymphocyte development and homeostasis. Recent studies have identified lymphatic endothelial cells (LECs) as a major source of IL-7 in LNs. Here, we report that LECs not only produce IL-7, but also express the IL-7 receptor chains IL-7Ra and CD132. Stimulation with recombinant IL-7 enhanced LEC in vitro activity and induced lymphangiogenesis in the cornea of wild-type (WT) mice. Whereas in IL-7Ra 2/2 mice, dermal lymphatic vessels (LVs)were abnormally organized and lymphatic drainage was compromised, transgenic overexpression of IL-7 in mice resulted in an expanded dermal LV network with increased drainage function. Moreover, systemic treatment with recombinant IL-7 enhanced lymphatic drainage in the skin of WT mice and of mice devoid of lymphocytes. Experiments in IL-7Rabone marrow chimeras demonstrated that the drainage-enhancing activity of IL-7 was exclusively dependent on IL-7Ra expression in stromal but not in hematopoietic cells. Finally, near-infrared in vivo imaging performed in IL-7Ra 2/2 mice revealed that the pumping activity of collecting vessels was normal but fluid uptake into lymphatic capillaries was defective. Overall, our data point toward an unexpected new role for IL-7 as a potential autocrine mediator of lymphatic drainage. (Blood. 2013;122(13):2271-2281

show abstract

“…Recurrence-Free Probability IL-7R has been shown to induce tumor growth and lymphangiogenesis through upregulation of VEGF-D. 34,35 Its ligand, IL-7, is produced by stromal and epithelial cells and plays a central role in T-cell development, in addition to providing a potent lymphocyte-survival factor through the JAK-STAT pathway. 36 The role of the IL-7/IL-7R axis in the tumor immune microenvironment in lung ADC warrants more investigation.…”

Section: Prognostic Immune Markers In Stage I Lung Adenocarcinomamentioning

confidence: 99%

Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence

Suzuki

Kadota

Sima

et al. 2013

JCO

185

182

View full text Add to dashboard Cite

A B S T R A C T PurposeMounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC). Patients and MethodsUsing tissue microarray and immunohistochemistry, we investigated eight types of tumorinfiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts). ResultsAlthough a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P ϭ .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P ϭ .004). High expression of tumor interleukin-12 receptor ␤2 (IL-12R␤2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P ϭ .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P ϭ .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors Յ 2 cm. ConclusionOur investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.

show abstract

Interleukin 7 upregulates vascular endothelial growth factor D in breast cancer cells and induces lymphangiogenesis in vivo

Abstract: IL-7 induced the lymphangiogenic properties of breast cancer cells, probably by upregulation of VEGF-D. This might have a significant impact on the lymphatic spread of breast cancer.

Cited by 43 publications

References 27 publications

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage

Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence

Contact Info

Product

Resources

About