Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer

Schoppmann, Sebastian F.; Fenzl, A.; Schindl, Monika; Bachleitner‐Hofmann, Thomas; Nagy, Katalin; Gnant, Michael; Horvat, Reinhard; Jakesz, R.; Birner, Peter

doi:10.1007/s10549-006-9190-3

Cited by 99 publications

(75 citation statements)

References 32 publications

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“…Previous descriptive studies reported correlations between HIF-1α expression and VEGF-C, FGF-2, and PDGF-B in breast cancer (12,20), gastric carcinoma (21), squamous cell carcinoma (14,17), and mesothelioma (31). Importantly, HIF-1α levels had prognostic value in LN-negative breast carcinomas (13).…”

Section: Discussionmentioning

confidence: 89%

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Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Schito

Rey²,

Tafani

et al. 2012

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

193

167

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Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.lymph node | orthotopic transplantation | triple-negative breast cancer M etastasis is the major cause of mortality in breast cancer patients (1). Metastatic dissemination of cancer cells from the primary tumor may occur via blood vessels or lymphatic vessels (LVs). In breast cancer, the most clinically important predictor of distant organ metastasis and patient mortality is the presence and extent of axillary lymph node (LN) metastasis (1). Increased density of peritumoral and intratumoral LVs in breast cancer is significantly associated with LN metastasis and patient mortality (2). Two members of the vascular endothelial growth factor (VEGF) family, VEGF-C and VEGF-D, bind to VEGF receptor 3 on the surface of lymphatic endothelial cells (LECs) to stimulate growth of LVs (lymphangiogenesis) and cancer cell metastasis to LNs and distant sites (3, 4). VEGF-A, which primarily stimulates blood vessel angiogenesis, promotes lymphangiogenesis and LN metastasis, and members of the angiopoietin, FGF, insulin-like growth factor (IGF), and PDGF families also have been reported to promote lymphangiogenesis and metastasis (1, 5).Intratumoral hypoxia is a common finding in breast cancer, and severe hypoxia [pO 2 <10 mm Hg (∼1.5% O 2 )] is associated with a significantly increased risk of metastasis and patient mortality (6). A major mechanism by which hypoxia promotes metastasis is through the hypoxia-inducible factors (HIFs), which activate the transcription of genes that play key roles in many critical aspects of cancer biology, including angiogenesis, metabolic reprogramming, epithelial-mesenchymal transition, and tissue invasion (7). HIFs are heterodimers composed of an O 2 -regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit (7). HIF-1α is required for vascular metastasis from breast to lung in autochthonous (8) and orthotopic transplantation (9-11) mouse models.Clinical studies h...

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Section: Discussionmentioning

confidence: 89%

“…Clinical studies have found that increased HIF-1α levels in primary breast tumors are significantly associated with peritumoral LV density (12) and patient mortality (13). HIF-1α levels also were associated with LN metastasis in esophageal cancer (14).…”

mentioning

confidence: 99%

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Schito

Rey²,

Tafani

et al. 2012

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

193

167

View full text Add to dashboard Cite

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“…The present study also demonstrated the correlation between both VEGF-C and VEGF-A to LVD and MVD, thus suggesting the two growth factors to be involved in both angiogenesis and lymphangiogenesis. On the other hand, the HIF-1· expression was demonstrated to correlate with the VEGF-C expression and lymphatic microvessel density in breast cancer (73) and oral squamous cell carcinoma (74). These findings suggested that Akt activation also contributes to lymphangiogenesis via VEGF-A and -C and HIF-1· expression.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer

et al. 2010

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“…Several previous reports have shown that HIF-· correlates with metastasis and distant recurrence (12)(13)(14)(15) and also correlates with VEGF-C expression and lymphangiogenesis in breast cancer (41). Therefore, we hypothesize that Tß4 may help regulate the process of lymph node metastasis due to its strong correlation with HIF-· expression.…”

Section: (77) -------------------------------------------------mentioning

confidence: 70%

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

Cho¹

2010

Oncol Rep

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Abstract. Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1· and HIF-2·, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin ß4 (Tß4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-· with Tß4 and the intracellular functional roles of Tß4 on HIF-· activation. We examined HIF-1·, HIF-2· and Tß4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1· and HIF-2· strongly correlates with Tß4 expression (P≤0.0001) and overexpression of Tß4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tß4 protein, which then affects HIF-· activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tß4 and HIF-· activities were reduced by interference of Tß4 expression using Tß4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tß4 is strongly associated with HIF-1· and HIF-2· expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-· activation and induction of VEGF-A. Ultimately, these results highlight Tß4 as a potentially therapeutic target in malignant cancers.

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Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer

Cited by 99 publications

References 32 publications

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

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