Cilengitide inhibits progression of experimental breast cancer bone metastases as imaged noninvasively using VCT, MRI and DCE‐MRI in a longitudinal <i>in vivo</i> study

Bäuerle, Tobias; Komljenovic, Dorde; Merz, Maximilian; Berger, Martin R.; Goodman, Simon L.; Semmler, Willi

doi:10.1002/ijc.25563

Cited by 76 publications

(72 citation statements)

References 56 publications

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“…In line with this observation, our data showed that α v β 3 /α v β 5 inhibition by cilengitide resulted in a significant decrease in proliferation of MDA-MB-231 cells in vitro. Correspondingly, previous studies have suggested a direct anti-tumor activity of this compound (14,16,30) and the growth of well-established bone metastases was found to decrease by cilengitide (20). We previously confirmed that α v β 5 is the primary α v integrin expressed in MDA-MB-231 cells suggesting that the anti-tumor effect occurred due to the inhibition of this integrin rather than α v β 3 (20).…”

Section: A B Discussionsupporting

confidence: 69%

“…Correspondingly, previous studies have suggested a direct anti-tumor activity of this compound (14,16,30) and the growth of well-established bone metastases was found to decrease by cilengitide (20). We previously confirmed that α v β 5 is the primary α v integrin expressed in MDA-MB-231 cells suggesting that the anti-tumor effect occurred due to the inhibition of this integrin rather than α v β 3 (20). However, the observed reduction in soft tissue component volumes after adjuvant cilengitide treatment may also be a consequence of the anti-angiogenic effect resulting from the inhibition of α v β 3 and α v β 5 on the endothelial of tumor vessels (14).…”

Section: A B Discussionmentioning

confidence: 60%

“…Recently, we demonstrated that the inhibition of α v β 3 /α v β 5 integrins by cilengitide reduced bone resorption and soft tissue tumor growth in well-established experimental breast cancer bone metastases (20). However, the effect of the inhibition of α v β 3 /α v β 5 integrins during the processes of bone colonization by breast cancer cells is unknown, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Cilengitide inhibits metastatic bone colonization in a nude rat model

et al. 2011

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Abstract. Integrins α v β 3 and α v β 5 are considered to play an important role in the pathogenesis of breast cancer bone metastases. This study investigates the effects of the α v β 3 /α v β 5 integrin-specific inhibitor cilengitide during early metastatic bone colonization. The impact of cilengitide on the migration, invasion and proliferation of MDA-MB-231 human breast carcinoma cells as well as on bone resorption by osteoclasts was investigated in vitro. For in vivo experiments, nude rats were treated with cilengitide for 30 days starting one day after site-specific tumor cell inoculation in the hind leg, and the course of metastatic changes in bone was followed using flatpanel volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). Vascular changes in bone metastases were investigated using dynamic contrast-enhanced (DCE-) MRI-derived parameters amplitude A and exchange rate coefficient k ep . In vitro, cilengitide treatment resulted in a decrease in proliferation, migration and invasion of MDA-MB-231 cells, as well as of osteoclast activity. In vivo, the development of bone metastasis in the hind leg of rats was not prevented by adjuvant cilengitide treatment, but cilengitide reduced the volumes of osteolytic lesions and respective soft tissue tumors of developing bone metastases as assessed with VCT and MRI, respectively. DCE-MRI revealed significant changes in the A and k ep parameters including decreased relative blood volume and increased vessel permeability after cilengitide treatment indicating vessel remodeling. In conclusion, during early pathogenic processes of bone colonization, cilengitide treatment exerted effects on tumor cells, osteoclasts and vasculature reducing the skeletal lesion size of experimental skeletal metastases.

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Section: A B Discussionsupporting

confidence: 69%

Section: A B Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Cilengitide inhibits metastatic bone colonization in a nude rat model

et al. 2011

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“…TSU68, a small molecule inhibiting VEGFR1, PDGFRβ and FGFR1 has been shown to suppress CXCL1/CXCR2-dependent niche formation in the liver by inhibition of the inflammatory response through reduction of CXCL1 and IL12 (137). Furthermore, antibodies directed against αv on breast cancer cells prevented metastasis to other organs, but not to the lung (138,139,140). However, a serious limitation for translational research is the complexicity of pre-metastatic and metastatic niches with respect to its architecture and the interplay between secreted factors and cellular components, resulting in difficulties in setting up in vitro systems for its recapitulation for discovery of inhibitory molecules.…”

Section: Translational Aspectsmentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

168

133

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Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

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“…24,26 Most recently, cilengitide has been shown to reduce the size of breast cancer bone metastases in a nude rat model and increase blood vessel permeability on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). 27,28 ILP with melphalan and TNF is used as salvage therapy in patients with distributed malignant melanoma or soft tissue sarcoma, and a response rate of 76% has been reported in locally advanced soft tissue sarcoma. 29 We have previously shown in the ILP system that the alkylating agent melphalan primarily induces tumor cell death while TNF inflicts tumor vascular damage and endothelial cell death.…”

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confidence: 99%

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Hagen

Seynhaeve

Wiel-Ambagtsheer

et al. 2012

Intl Journal of Cancer

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Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-a is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.Since the continued growth of solid tumors requires angiogenesis, an anti-angiogenic approach to cancer therapy is logical. Since angiogenesis is mediated in part by adhesion receptors of the integrin family, including the alpha-V (aV) integrins, 1,2 there is a strong rationale for assessing the effects of integrin inhibitors in cancer treatment. Cilengitide (EMD

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Cilengitide inhibits progression of experimental breast cancer bone metastases as imaged noninvasively using VCT, MRI and DCE‐MRI in a longitudinal in vivo study

Cited by 76 publications

References 56 publications

Cilengitide inhibits metastatic bone colonization in a nude rat model

Cilengitide inhibits metastatic bone colonization in a nude rat model

The Multiple Roles of Exosomes in Metastasis

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

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