Induction of a proinflammatory program in normal human thyrocytes by the
            <i>RET/PTC1</i>
            oncogene

Borrello, Maria Grazia; Alberti, Luisella; Fischer, Andrew H.; Degl’Innocenti, Debora; Ferrario, Cristina; Gariboldi, Manuela; Marchesi, Federica; Allavena, Paola; Greco, Angela; Collini, Paola; Pilotti, Silvana; Cassinelli, Giuliana; Bressan, Paola; Fugazzola, Laura; Mantovani, Alberto

doi:10.1073/pnas.0503039102

Cited by 306 publications

(280 citation statements)

References 43 publications

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“…Collectively, the gene expression data support the notion that TIMP3 may exert an oncosuppressor role in PTC, as also proposed by previous studies. In fact, TIMP3 gene was found to be downregulated in primary thyrocytes infected with RET/PTC1 retroviral vector with respect to uninfected cells (Borrello et al, 2005). Moreover, TIMP3 was identified within a group of tumor-suppressor genes (also including SLC5A8, DAPK and RARb2) hypermethylated in a consistent fraction (53%) of PTCs in association with tumor aggressiveness and BRAF mutation (Hu et al, 2006).…”

Section: Discussionmentioning

confidence: 96%

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

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Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

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Section: Discussionmentioning

confidence: 96%

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

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“…Thus, an abnormal HER2 activation such as that occurring in tumors with HER2 amplification could generate an inflammatory environment, as has been described for other oncogenes such as RET/PTC1 in thyroid cancer, 21 RAF in melanoma, and MYC in pancreatic tumors. 22 Considering that the PI3K/AKT pathway is common to different membrane receptors, tumor cell signals other than HER2 may contribute to CCL2 expression albeit to a lesser extent in HER2-addicted BCs. In these tumors, signal derived from HER2 homodimerization and its heterodimerization with EGFR and HER3 would be the main driver of CCL2 production.…”

Section: Discussionmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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“…CXCL8) [9,10]. The tyrosine kinase RET, a prototypic transforming oncogene in human papillary carcinoma of the thyroid, activates in normal primary human thyrocytes an inflammatory programme, where chemokines are the most abundant category in addition to other cytokines and reactive mediators [11]. Expressed chemokines include CCL2, CCL20, angiogenic CXC ligands, CXCL12 and its receptor CXCR4.…”

Section: Chemokines As Targets Of Genetic Lesions Causing Cancermentioning

confidence: 99%

Chemokines in cancer related inflammation

Allavena

Germano

Marchesi

et al. 2011

Experimental Cell Research

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Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis.Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies

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Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

Cited by 306 publications

References 43 publications

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Chemokines in cancer related inflammation

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