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Harnessing Induced Essentiality: Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. BC Canc Res Ctr, Canada.
BC Canc Res Ctr, Canada.
BC Canc Res Ctr, Canada.
BC Canc Res Ctr, Canada.
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2019 (English)In: Cancers, ISSN 2072-6694, CANCERS, Vol. 11, no 7, article id 1002Article in journal (Refereed) Published
Abstract [en]

Triple Negative Breast Cancer (TNBC) is aggressive, metastatic and drug-resistant, limiting the spectrum of effective therapeutic options for breast cancer patients. To date, anti-angiogenic agents have had limited success in the treatment of systemic breast cancer, possibly due to the exacerbation of tumor hypoxia and increased metastasis. Hypoxia drives increased expression of downstream effectors, including Carbonic Anhydrase IX (CAIX), a critical functional component of the pro-survival machinery required by hypoxic tumor cells. Here, we used the highly metastatic, CAIX-positive MDA-MB-231 LM2-4 orthotopic model of TNBC to investigate whether combinatorial targeting of CAIX and angiogenesis impacts tumor growth and metastasis in vivo to improve efficacy. The administration of a small molecule inhibitor of CAIX, SLC-0111, significantly reduced overall metastatic burden, whereas exposure to sunitinib increased hypoxia and CAIX expression in primary tumors, and failed to inhibit metastasis. The administration of SLC-0111 significantly decreased primary tumor vascular density and permeability, and reduced metastasis to the lung and liver. Furthermore, combining sunitinib and SLC-0111 significantly reduced both primary tumor growth and sunitinib-induced metastasis to the lung. Our findings suggest that targeting angiogenesis and hypoxia effectors in combination holds promise as a novel rational strategy for the effective treatment of patients with TNBC.

Place, publisher, year, edition, pages
MDPI, 2019. Vol. 11, no 7, article id 1002
Keywords [en]
angiogenesis; carbonic anhydrase IX; hypoxia; metastasis; resistance; sunitinib; triple negative breast cancer
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-161212DOI: 10.3390/cancers11071002ISI: 000479322800113PubMedID: 31319613Scopus ID: 2-s2.0-85071013947OAI: oai:DiVA.org:liu-161212DiVA, id: diva2:1365656
Note

Funding Agencies|Swedish Research Council (Vetenskapsradet)Swedish Research Council [537-2013-7467]; Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR) [143318]; Canadian Cancer Society Research Institute (CCSRI) [703191]

Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-31Bibliographically approved

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Hedlund, Eva-MariaJensen, Lasse
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Division of Cardiovascular MedicineFaculty of Medicine and Health SciencesDepartment of Clinical Pharmacology
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