Contrasting effects of sunitinib within in vivo models of metastasis

Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both...

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Published in:	Angiogenesis (London) Vol. 15; no. 4; pp. 623 - 641
Main Authors:	Welti, Jonathan C., Powles, Thomas, Foo, Shane, Gourlaouen, Morgane, Preece, Natasha, Foster, Julie, Frentzas, Sophia, Bird, Demelza, Sharpe, Kevin, van Weverwijk, Antoinette, Robertson, David, Soffe, Julie, Erler, Janine T., Pili, Roberto, Springer, Caroline J., Mather, Stephen J., Reynolds, Andrew R.
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer Netherlands 01-12-2012 Springer Springer Nature B.V
Subjects:	Animals Antineoplastic Agents - therapeutic use Biological and medical sciences Biomedical and Life Sciences Biomedicine Blood and lymphatic vessels Cancer Research Cardiology Cardiology. Vascular system Cardiovascular system Cell Biology Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Indoles - therapeutic use Medical sciences Mice Mice, Inbred BALB C Neoplasm Metastasis - drug therapy Oncology Ophthalmology Original Paper Pharmacology. Drug treatments Positron-Emission Tomography Pyrroles - therapeutic use Sunitinib Tomography, X-Ray Computed Vasodilator agents. Cerebral vasodilators Resistance Breast Angiogenesis Metastasis Renal VEGF Antineoplastic agent Enzyme Tyrosine kinase inhibitor Transferases Enzyme inhibitor Cardiovascular disease Malignant tumor Sunitinib Multikinase inhibitor Antiangiogenic agent Protein-tyrosine kinase Cancer
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Summary:	Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0969-6970 1573-7209
DOI:	10.1007/s10456-012-9291-z