Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance

Stanton, Marissa J.; Dutta, Samikshan; Zhang, Heyu; Polavaram, Navatha S.; Leontovich, Alexey A.; Hönscheid, Pia; Sinicrope, Frank A.; Tindall, Donald J.; Muders, Michael H.; Datta, Kaustubh

doi:10.1158/0008-5472.can-11-3635

Cited by 80 publications

(100 citation statements)

References 51 publications

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“…30,31 In a breast cancer model, a similar antioxidant function of VEGF-C/NRP2 was observed. However, in this study, superoxide dismutase 3 was identified as the principal mediator.…”

Section: Vegf-c and Neurophilinmentioning

confidence: 65%

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

Wang

Tsai

2015

Exp Biol Med (Maywood)

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It has been shown in many clinical studies that the level of vascular endothelial growth factor-C (VEGF-C) positively correlates with lymph node metastasis. Nevertheless, beyond the canonical role of VEGF-C in stimulating lymphangiogenesis and thus promoting lymph node/distant metastasis, emerging evidence indicates that expression of VEGF-C contributes to various aspects of carcinogenicity via autocrine regulation. The newly identified functions of VEGF-C include but are not limited to proliferation, migration, invasion, and chemo-resistance. Besides tumor cell autocrine regulation, VEGF-C can also modulate the immune system such that tumor cells more easily escape immune surveillance. Therefore, understanding the functional roles and regulatory mechanisms related to the VEGF-C axis may lead to alternative strategies for cancer treatment. This mini-review will focus on summarizing recent discoveries regarding the unconventional functions of VEGF-C in cancer progression.

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“…30,31 In a breast cancer model, a similar antioxidant function of VEGF-C/NRP2 was observed. However, in this study, superoxide dismutase 3 was identified as the principal mediator.…”

Section: Vegf-c and Neurophilinmentioning

confidence: 65%

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

Wang

Tsai

2015

Exp Biol Med (Maywood)

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“…The autophagic flux can be reflected by the fold change in LC3-II levels with or without chloroquine. 10,11 We found that the fold change in LC3-II levels in cisplatin-resistant A2780/CP70 cells after lysosome inhibition via chloroquine was remarkably upregulated in response to cisplatin treatment, suggesting autophagy induction (Fig. 1A).…”

Section: Cisplatin Induces Autophagic Flux In Cisplatin-resistant Ovamentioning

confidence: 93%

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

et al. 2015

Autophagy

148

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Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatinresistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatinresistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

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“…However, this study did not investigate the contribution of specific NRP ligands and it is therefore not known if the mechanism is VEGF dependent. VEGF may also regulate autophagy because it has been shown that NRP2-mediated VEGFC signalling mediated by mTOR complex 1 activates an autophagic mechanism that combats chemotherapy-induced stress, which has implications for the role of VEGF signalling in therapy resistance 93 .…”

Section: Vegf-mediated Functions In Tumour Cellsmentioning

confidence: 99%

VEGF targets the tumour cell

2013

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The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

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Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance

Cited by 80 publications

References 51 publications

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

VEGF targets the tumour cell

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