The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

Doré-Savard, Louis; Lee, Esak; Kakkad, Samata; Popel, Aleksander S.; Bhujwalla, Zaver M.

doi:10.1038/srep39460

Cited by 25 publications

(25 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This indicates a deficiency in the disulfide-bonded form and in the total amount of these soluble factors in the secretome of ERO1 KO MDAMB231 m . Given that these are angiogenesis-related factors and are HIF-1 targets (Supplementary Table 2 ) [ 19 ], our results point to a role of ERO1 on a subset of secreted proteins which are angiogenesis-related.…”

Section: Resultsmentioning

confidence: 80%

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

et al. 2021

View full text Add to dashboard Cite

SummarySolid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.

show abstract

Section: Resultsmentioning

confidence: 80%

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Here we have described findings that identify an important role of IL-8 in crosstalk between TNBC and stroma and propose IL-8 as a potential therapeutic target in TNBC. The elevated IL-8 cytokine as a tumor microenvironment factor has also been identified in the interstitial fluid collected in a tumor-implanted microchamber in TNBC xenografts, but not in ER+ xenografts, suggesting its specificity for TNBC [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis

2017

Self Cite

View full text Add to dashboard Cite

Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB-231-CXCR2−/− tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231-CXCR2−/− tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDA-MB-231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components.

show abstract

“…This was reduced by CK666 treatment, with the number of mature branches that had been penetrated by tubulin also reduced. MDA MB231 release greater levels of VEGF-A versus MCF7 [ 44 , 46 ] therefore it would be expected that MDA MB231 to induce increased neurite formation as it is demonstrated that VEGF-A actions via VEGFR2 induce sensory neuron growth. However, VEGF-A alone did not induce increased collateral branching.…”

Section: Discussionmentioning

confidence: 99%

Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching

et al. 2017

View full text Add to dashboard Cite

The tumour and neuron interaction has a significant impact upon disease progression and the patients quality of life. In breast cancer patients, it is known that there is an interaction between the tumour microenvironment and the sensory neurons to influence the progression of cancer as well as pain, though these mechanisms still need to be clearly defined. Here it is demonstrated that in a rodent orthotopic model of breast cancer (MDA MB 231) there was an increase in nerve fibre innervation into the tumour microenvironment (protein gene product 9.5), which were calcitonin gene related peptide positive C fibre nociceptors. In contrast, there was a reduction in myelinated nerve fibres (NF200). A sensory neuronal cell line was cultured in response to conditioned media from MDA MB231 and MCF7 as well as vascular endothelial growth factor-A (VEGF-A). All these experimental conditions induced sensory neuronal growth, with increased formation of collateral axonal branches. Furthermore, it was demonstrated that MDA MB231 and VEGF-A induced sensory neuronal sensitisation in response to capsaicin a TRPV1 agonist. MDA MB231 induced neuronal growth was suppressed by VEGFR2 inhibition (ZM323881 and neutralising antibody DC101), in addition both MDA MB231 and VEGF-A induced neurite growth was attenuated by the inhibition of ARP2/3 complex through co-treatment with CK666. This demonstrates that breast cancer can interact with the sensory nervous system to drive neuritogenesis through a VEGF-A/VEGFR2/ARP2/3 mediated pathway.

show abstract

The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

Cited by 25 publications

References 51 publications

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis

Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching

Contact Info

Product

Resources

About