Nuclear Factor κB–Dependent Regulation of Angiogenesis, and Metastasis in an In Vivo Model of Thyroid Cancer Is Associated With Secreted Interleukin-8

Bauerle, Kevin T.; Schweppe, Rebecca E.; Lund, Gregory S.; Kotnis, Gregory; Deep, Gagan; Agarwal, Rajesh; Pozdeyev, Nikita; Wood, William M.; Haugen, Bryan R.

doi:10.1210/jc.2013-3636

Cited by 52 publications

(44 citation statements)

References 34 publications

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“…ATC tumors are characterized by their heterogeneity, complex mutational landscape, and poor expression of molecules that have previously been exploited as molecular and cellular targets (1, 32, 54). The prolonged survival achieved upon treatment of ATC inoculated mice with ICAM-1 CAR T was particularly notable when compared with previous treatment strategies in preclinical metastatic models using the same ATC cell line (55–57). The preclinical xenograft model used here is limited by the inability to monitor potential toxicity mediated by ICAM-1 CAR against non-tumor tissue.…”

Section: Discussionmentioning

confidence: 90%

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

Min

Shevlin

Vedvyas

et al. 2017

Clinical Cancer Research

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Purpose Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. Experimental Design ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and ‘off-tumor’ toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases. Results ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR-T cells mediated profound tumor killing that resulted in long term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models. Conclusions Our findings are the first demonstration of CAR T therapy for metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies.

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Section: Discussionmentioning

confidence: 90%

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

Min

Shevlin

Vedvyas

et al. 2017

Clinical Cancer Research

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“…The above concepts would fit with the observation that, in orthotopic nude mice, BCPAP cells produce tumors with an aggressive clinical behavior (as assessed by higher metastatic potential and reduced survival), while the cell lines including TPC-1 that secreted significantly lower levels of CXCL8 as compared to BCPAP did not establish tumors in mice [24].…”

Section: Discussionmentioning

confidence: 91%

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

et al. 2015

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CXCL8 is secreted by both normal human thyrocytes (NHT) and thyroid cancer cell lines. CXCL8 displays several tumor-promoting effects and recent evidences indicate that its concentrations within the tumor microenvironment can impact the clinical course of the malignancy. Aim of this study was to compare the basal secretion of CXCL8 among NHT and thyroid cancer cell lines (TPC-1 and BCPAP), and to assess the specific cell response to TNF-α in terms of CXCL8 secretion. NHT primary cultures, TPC-1 and BCPAP cell lines were cultured with or without TNF-α (0, 0.1, 1, 10, and 100 ng/ml). CXCL8 levels were measured in the cell supernatants after 24 h. In basal condition, significant differences in the mean levels of CXCL8 were observed among the three cell types: NHT (110.5 ± 56.2 pg/ml), TPC1 (467.4 ± 43.2 pg/ml), and BCPAP (1731.8 ± 493.3 pg/ml), (F = 35.06; p < 0.0001). TNF-α significantly and in a dose-response manner induced CXCL8 secretion in NHT (F = 25.53; p < 0.00001), TPC-1 (F = 13.38; p < 0.0001), and BCPAP (F = 9.88; p < 0.001) cells. The magnitude of the TNF-α effect (fold-increase vs. basal level of CXCL8) differed significantly among the three cell types (F = 10.47; p < 0.0001). BCPAP were identified as the cells showing the highest basal secretion of CXCL8 and the less responsive to TNF-α. NHT, TPC-1, and BCPAP display significant differences in the secretion of both basal and TNF-α-induced CXCL8 secretion. These results indicate that the mechanisms regulating the secretion of CXCL8 differ in tumor cells harboring different genetic alterations suggesting that specific strategies aimed at inhibiting CXCL8 secretion will be required.

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“…43 In a model of orthotopic TC xenograft in nude mice, CXCL8/IL-8 was involved in tumor growth and progression, at least in part due to the activation of the NF-kB pathway. 44 In addition to TC themselves, also the tumor-infiltrating immune cells can be a source of chemokines. Indeed, MCderived CXCL8/IL-8 in vitro induced EMT features and stemness in human TC cells.…”

Section: Chemokinesmentioning

confidence: 99%

The immune network in thyroid cancer

2016

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The immune system plays critical roles in tumor prevention, but also in its initiation and progression. Tumors are subjected to immunosurveillance, but cancer cells generate an immunosuppressive microenvironment that favors their escape from immune-mediated elimination. During chronic inflammation, immune cells can contribute to the formation and progression of tumors by producing mitogenic, prosurvival, proangiogenic and lymphangiogenic factors. Thyroid cancer is the most frequent type of endocrine neoplasia and is the most rapidly increasing cancer in the US. In this review, we discuss recent findings on how different immune cells and mediators can contribute to thyroid cancer development and progression.

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Nuclear Factor κB–Dependent Regulation of Angiogenesis, and Metastasis in an In Vivo Model of Thyroid Cancer Is Associated With Secreted Interleukin-8

Abstract: These studies suggest that NF-κB signaling is a key regulator of angiogenesis and growth of primary and metastatic thyroid cancer, and that IL-8 may be an important downstream mediator of NF-κB signaling in advanced thyroid cancer growth and progression.

Cited by 52 publications

References 34 publications

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

The immune network in thyroid cancer

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