Chemotherapy Enhances Metastasis Formation via VEGFR-1–Expressing Endothelial Cells

Daenen, Laura G.M.; Roodhart, Jeanine M.L.; Amersfoort, Miranda van; Dehnad, Mantre; Roessingh, Wijnand M.; Ulfman, Laurien H.; Derksen, Patrick W.B.; Voest, Emile E.

doi:10.1158/0008-5472.can-11-0627

Cited by 154 publications

(151 citation statements)

References 29 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…The host's response to several chemotherapy drugs has recently been investigated in various studies (11,25,26,(41)(42)(43). The first study reported that administration of cytotoxic-like vascular disrupting agents to non-tumor-bearing mice induced a rapid CEP mobilization (32).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously reported that chemotherapy induces molecular host factors that can contribute to tumor cell growth and tumor colonization in the lungs (11,(23)(24)(25)(26). For example, matrix metallopeptidase 9 (MMP9) secreted from bone marrow-derived cells (BMDC) that colonize paclitaxel-treated tumors may explain why mice primed with paclitaxel chemotherapy succumb to metastasis earlier than mice treated with vehicle control (25).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Alishekevitz

Bril

Loven

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-VEGF-A therapy in this context has not been fully explored. We, therefore, used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice, including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found at metastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patients with cancer. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy. Mol Cancer Ther; 13(1); 202-13. Ó2013 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Alishekevitz

Bril

Loven

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Daenen and colleagues showed that paclitaxel and cisplatin given to mice 4 days before intravenous tumor cell inoculation could lead to an upregulation of VEGFR-1 on endothelial cells, which, in turn, coincided with increased metastasis. Specific VEGFR-1 inhibitors were then shown to mitigate the treatment-mediated metastasis and extend survival (32).…”

Section: Mechanisms Of Timmentioning

confidence: 99%

Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis

Ebos

2015

Cancer Research

View full text Add to dashboard Cite

The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits. The paradox of treatment-induced metastasis (TIM) is not new. Supporting preclinical studies span decades, but are often overlooked. With recent evidence of prometastatic effects following treatment with tar-

show abstract

“…For example, VEGFR-1 could be found on tumor cells of different tissue origin, where it promotes tumor growth rather than stimulates tumor angiogenesis (8). In animal tumor models, both VEGFR-1 and -2 are implicated in the development of established micrometastases (9); however, it is VEGFR-1 that is critically involved in the preparation of metastatic niche (10). In view of such differential involvement of VEGFR-1 and VEGFR-2 in the onset and progression of cancer, it would be logical to expect that each receptor might be an important biomarker for the selection of an appropriate cancer treatment or for monitoring the response to therapy in individual patients.…”

mentioning

confidence: 99%

Selective Imaging of VEGFR-1 and VEGFR-2 Using ⁸⁹Zr-Labeled Single-Chain VEGF Mutants

et al. 2016

View full text Add to dashboard Cite

Vascular endothelial growth factor-A (VEGF-A) acts via 2 vascular endothelial growth factor receptors, VEGFR-1 and VEGFR-2, that play important and distinct roles in tumor biology. We reasoned that selective imaging of these receptors could provide unique information for diagnostics and for monitoring and optimizing responses to anticancer therapy, including antiangiogenic therapy. Herein, we report the development of 2 first-in-class 89 Zr-labeled PET tracers that enable the selective imaging of VEGFR-1 and VEGFR-2. Methods: Functionally active mutants of scVEGF (an engineered single-chain version of pan-receptor VEGF-A with an N-terminal cysteine-containing tag for site-specific conjugation), named scVR1 and scVR2 with enhanced affinity to, respectively, VEGFR-1 and VEGFR-2, were constructed. Parental scVEGF and its receptor-specific mutants were site-specifically derivatized with the 89 Zr chelator desferroxamine B via a 3.4-kDa PEG linker. 89 Zr labeling of the desferroxamine B conjugates furnished scV/Zr, scVR1/Zr, and scVR2/Zr tracers with high radiochemical yield (.87%), high specific activity ($9.8 MBq/ nmol), and purity (.99%). Tracers were tested in an orthotopic breast cancer model using 4T1luc-bearing syngeneic BALB/c mice. For testing tracer specificity, tracers were coinjected with an excess of cold proteins of the same or opposite receptor specificity or pan-receptor scVEGF. PET imaging, biodistribution, and dosimetry studies in mice, as well as immunohistochemical analysis of harvested tumors, were performed. Results: All tracers rapidly accumulated in orthotopic 4T1luc tumors, allowing for the successful PET imaging of the tumors as early as 2 h after injection. Blocking experiments with an excess of pan-receptor or receptorspecific cold proteins indicated that more than 80% of tracer tumor uptake is VEGFR-mediated, whereas uptake in all major organs is not affected by blocking within the margin of error. Critically, blocking experiments indicated that VEGFR-mediated tumor uptake of scVR1/Zr and scVR2/Zr was mediated exclusively by the corresponding receptor, VEGFR-1 or VEGFR-2, respectively. In contrast, uptake of pan-receptor scV/Zr was mediated by both VEGFR-1 and VEGFR-2 at an approximately 2:1 ratio. Conclusion: First-in-class selective PET tracers for imaging VEGFR-1 and VEGFR-2 were constructed and successfully validated in an orthotopic murine tumor model.

show abstract

Chemotherapy Enhances Metastasis Formation via VEGFR-1–Expressing Endothelial Cells

Cited by 154 publications

References 29 publications

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis

Selective Imaging of VEGFR-1 and VEGFR-2 Using ⁸⁹Zr-Labeled Single-Chain VEGF Mutants

Contact Info

Product

Resources

About

Chemotherapy Enhances Metastasis Formation via VEGFR-1–Expressing Endothelial Cells

Cited by 154 publications

References 29 publications

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis

Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants

Contact Info

Product

Resources

About

Selective Imaging of VEGFR-1 and VEGFR-2 Using ⁸⁹Zr-Labeled Single-Chain VEGF Mutants