Contrasting effects of sunitinib within in vivo models of metastasis

Jonathan C Welti; Thomas Powles; Shane Foo; Morgane Gourlaouen; Natasha Preece; Julie Foster; Sophia Frentzas; Demelza Bird; Kevin Sharpe; Antoinette van Weverwijk; David Robertson; Julie Soffe; Janine T Erler; Roberto Pili; Caroline J Springer; Stephen J Mather; Andrew R Reynolds

doi:10.1007/s10456-012-9291-z

Contrasting effects of sunitinib within in vivo models of metastasis

Jonathan C Welti, Thomas Powles, Shane Foo, Morgane Gourlaouen, Natasha Preece, Julie Foster, Sophia Frentzas, Demelza Bird, Kevin Sharpe, Antoinette van Weverwijk, David Robertson, Julie Soffe, Janine T Erler, Roberto Pili, Caroline J Springer, Stephen J Mather, Andrew R Reynolds

46 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Angiogenesis
Vol/bind	15
Udgave nummer	4
Sider (fra-til)	623-41
Antal sider	19
ISSN	0969-6970
DOI	https://doi.org/10.1007/s10456-012-9291-z
Status	Udgivet - dec. 2012
Udgivet eksternt	Ja

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10.1007/s10456-012-9291-z

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Welti, J. C., Powles, T., Foo, S., Gourlaouen, M., Preece, N., Foster, J., Frentzas, S., Bird, D., Sharpe, K., van Weverwijk, A., Robertson, D., Soffe, J., Erler, J. T., Pili, R., Springer, C. J., Mather, S. J., & Reynolds, A. R. (2012). Contrasting effects of sunitinib within in vivo models of metastasis. Angiogenesis, 15(4), 623-41. https://doi.org/10.1007/s10456-012-9291-z

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title = "Contrasting effects of sunitinib within in vivo models of metastasis",

abstract = "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.",

keywords = "Animals, Antineoplastic Agents, Indoles, Mice, Mice, Inbred BALB C, Neoplasm Metastasis, Positron-Emission Tomography, Pyrroles, Tomography, X-Ray Computed",

author = "Welti, {Jonathan C} and Thomas Powles and Shane Foo and Morgane Gourlaouen and Natasha Preece and Julie Foster and Sophia Frentzas and Demelza Bird and Kevin Sharpe and {van Weverwijk}, Antoinette and David Robertson and Julie Soffe and Erler, {Janine T} and Roberto Pili and Springer, {Caroline J} and Mather, {Stephen J} and Reynolds, {Andrew R}",

year = "2012",

month = dec,

doi = "10.1007/s10456-012-9291-z",

language = "English",

volume = "15",

pages = "623--41",

journal = "Angiogenesis",

issn = "0969-6970",

publisher = "Springer",

number = "4",

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TY - JOUR

T1 - Contrasting effects of sunitinib within in vivo models of metastasis

AU - Welti, Jonathan C

AU - Powles, Thomas

AU - Foo, Shane

AU - Gourlaouen, Morgane

AU - Preece, Natasha

AU - Foster, Julie

AU - Frentzas, Sophia

AU - Bird, Demelza

AU - Sharpe, Kevin

AU - van Weverwijk, Antoinette

AU - Robertson, David

AU - Soffe, Julie

AU - Erler, Janine T

AU - Pili, Roberto

AU - Springer, Caroline J

AU - Mather, Stephen J

AU - Reynolds, Andrew R

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Indoles

KW - Mice

KW - Mice, Inbred BALB C

KW - Neoplasm Metastasis

KW - Positron-Emission Tomography

KW - Pyrroles

KW - Tomography, X-Ray Computed

U2 - 10.1007/s10456-012-9291-z

DO - 10.1007/s10456-012-9291-z

M3 - Journal article

C2 - 22843200

SN - 0969-6970

VL - 15

SP - 623

EP - 641

JO - Angiogenesis

JF - Angiogenesis

IS - 4

ER -

Contrasting effects of sunitinib within in vivo models of metastasis

Abstract

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