Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

Bièche, Ivan; Vacher, Sophie; Vallerand, David; Richon, Sophie; Hatem, Rana; Plater, Ludmilla de; Dahmani, Ahmed; Némati, Fariba; Angevin, Eric; Marangoni, Elisabetta; Roman-Roman, Sergio; Decaudin, Didier; Dangles‐Marie, Virginie

doi:10.1186/1471-2407-14-178

Cited by 23 publications

(27 citation statements)

References 29 publications

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“…interaction between VEGFA and the two receptors, FLT1 and KDR, though which downstream signaling for angiogenesis is activated (5,21). Previous studies have produced contradicting results regarding the prognostic significance of VEGFA, FLT1 and KDR expression in lung cancer (12,13).…”

Section: A B C D Ementioning

confidence: 99%

“…Among various pro-angiogenic factors, VEGFA has been identified to be a predominant regulator of tumor angiogenesis (5). High expression of these three genes has been identified in non-small cell lung cancer xenografts compared with xenografts originating from other sites (5), indicating that these three factors may be significant in lung cancer progression. Indeed, VEGFA (6)(7)(8), FLT1 (9,10) and KDR (11,12) have all been demonstrated to promote lung cancer progression.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of combining VEGFA, FLT1 and KDR mRNA expression in lung cancer

Zhang¹,

McCrudden

Kwok³

2015

Oncology Letters

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Abstract. Angiogenesis is important in cancer progression. Promising results in clinical trials have indicated that targeting vascular epidermal growth factor (VEGF) signaling may prolong lung cancer patient survival. In particular, various studies have implicated VEGFA as a potential prognostic marker in lung cancer, although prognostication using the expression of VEGF receptors (VEGFRs), such as fms-related tyrosine kinase 1 (FLT1; also known as VEGFR1) and kinase insert domain receptor (KDR; also known as VEGFR2), has produced varied results in different lung cancer studies. The present study aimed to investigate the prognostic significance of these three factors, alone or in combination. mRNA expression data were extracted from four independent lung cancer cohorts totaling 583 patients, and the association between mRNA expression and survival was investigated by performing statistical analyses. When VEGFA, FLT1 and KDR expression were considered alone, only VEGFA demonstrated a significant association with patient survival consistently across all four datasets (P<0.05). Patients with a high expression of VEGFA and one of the two receptors were associated with significantly worse survival than patients expressing low levels of VEGFA and the particular receptor (P<0.05). Notably, patients with a high level expression of all three genes in their tumor specimens were associated with a significantly shorter survival time compared with patients exhibiting a low level expression of one, two or all three genes (P<0.05). The results indicate that a high level of VEGFA expression and its receptors may be required for cancer progression. Therefore, these three factors should be considered together as a prognostic indicator for lung cancer patients.

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Section: A B C D Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic significance of combining VEGFA, FLT1 and KDR mRNA expression in lung cancer

Zhang¹,

McCrudden

Kwok³

2015

Oncology Letters

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“…As VEGFR2 is mainly expressed by vascular endothelial cells (Supporting Information Fig. S4), its expression in PDX models was determined using murine specific RT‐PCR primers . Similar percentages of targets overexpression were found in PDX and patients tumors.…”

Section: Resultsmentioning

confidence: 80%

Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

Hatem

Labiod

Château-Joubert

et al. 2016

Intl Journal of Cancer

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The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers (BC) but its role in estrogen receptor (ER) negative tumors is unknown. Here we investigated the expression of RET in breast cancer patients tumors and patient-derived xenografts (PDX) and evaluated the therapeutic potential of Vandetanib, a tyrosin kinase inhibitor with strong activity against RET, EGFR and VEGFR2, in ER negative breast cancer PDX. The RT-PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX, showed elevated levels of RET in ER1 and HER21 subtypes and in a small subgroup of triple-negative breast cancers (TNBC). The activity of Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER21 BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in PDX models with high expression of RET or EGFR. The effect was associated with inhibition of RET/EGFR phosphorylation and MAP kinase pathway and increased necrosis. In a PDX model with no expression of RET nor EGFR, Vandetanib slowed tumor growth without inducing tumor regression. In addition, treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested, suggesting inhibition of tumor vascularization. In summary, these preclinical results suggest that Vandetanib treatment could be useful for patients with ER negative breast cancers overexpressing Vandetanib's main targets.Breast cancers are heterogeneous, with a multitude of molecular alterations supporting their malignant progression. RET overexpression was found in 33% of ER1 tumors and 10% ER-tumors. 6 In addition, it has been shown that anti-RET therapies might be used in ER1 tumors to potentiate the effect of endocrine treatments in preclinical models. 7,8 In another study performed on 108 breast cancer patients, expression of RET was found in high percentages in HER21, triple-negative and ER positive tumors. 9 Therefore, RET seems to be a promising therapeutic target in breast cancer, irrespectively of molecular subtype. If RET has been mainly investigated in luminal breast cancer, no preclinical evidence exists that it is a relevant target in the subset of ER negative tumors overexpressing RET.

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“…Total RNA was prepared as previously described . Quantitative values were obtained from the cycle number (Ct value) using ABI Prism 7,900 Sequence Detection System (Perkin‐Elmer Applied Biosystems, CA) and PE Biosystems analysis software according to the manufacturer's manuals.…”

Section: Methodsmentioning

confidence: 99%

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

Cacheux

Lièvre

Richon

et al. 2019

Intl Journal of Cancer

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Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer‐associated fibroblasts and that IGF2 secreted by cancer‐associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer‐associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

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Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

Cited by 23 publications

References 29 publications

Prognostic significance of combining VEGFA, FLT1 and KDR mRNA expression in lung cancer

Prognostic significance of combining VEGFA, FLT1 and KDR mRNA expression in lung cancer

Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

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