Murine breast cancer feed arteries are thin-walled with reduced alpha(1A)-adrenoceptor expression and attenuated sympathetic vasocontraction

作者：Froelunde Anne Sofie; Ohlenbusch Marit; Hansen Kristoffer B; Jessen Nicolai; Kim Sukhan; Boedtkjer Ebbe^*

来源：Breast Cancer Research, 2018, 20(1): 20.

DOI：10.1186/s13058-018-0952-8

• Adrenergic receptors
• Arterial structure
• Breast cancer
• Sympathetic nerve activity
• Tumor microenvironment

Background: Perfusion of breast cancer tissue limits oxygen availability and metabolism but angiogenesis inhibitors have hitherto been unsuccessful for breast cancer therapy. In order to identify abnormalities and possible therapeutic targets in mature cancer arteries, we here characterize the structure and function of cancer feed arteries and corresponding control arteries from female FVB/N mice with ErbB2-induced breast cancer.
Methods: We investigated the contractile function of breast cancer feed arteries and matched control arteries by isometric myography and evaluated membrane potentials and intracellular [Ca2+] using sharp electrodes and fluorescence microscopy, respectively. Arterial wall structure is assessed by transmission light microscopy of arteries mounted in wire myographs and by evaluation of histological sections using the unbiased stereological disector technique. We determined the expression of messenger RNA by reverse transcription and quantitative polymerase chain reaction and studied receptor expression by confocal microscopy of arteries labelled with the BODIPY-tagged alpha(1)-adrenoceptor antagonist prazosin.
Results: Breast cancer feed arteries are thin-walled and produce lower tension than control arteries of similar diameter in response to norepinephrine, thromboxane-analog U46619, endothelin-1, and depolarization with elevated [K+]. Fewer layers of similarly-sized vascular smooth muscle cells explain the reduced media thickness of breast cancer arteries. Evidenced by lower media stress, norepinephrine-induced and thromboxane-induced tension development of breast cancer arteries is reduced more than is explained by the thinner media. Conversely, media stress during stimulation with endothelin-1 and elevated [K+] is similar between breast cancer and control arteries. Correspondingly, vascular smooth muscle cell depolarizations and intracellular Ca2+ responses are attenuated in breast cancer feed arteries during norepinephrine but not during endothelin-1 stimulation. Protein expression of alpha(1)-adrenoceptors and messenger RNA levels for alpha(1A)-adrenoceptors are lower in breast cancer arteries than control arteries. Sympathetic vasocontraction elicited by electrical field stimulation is inhibited by alpha(1)-adrenoceptor blockade and reduced in breast cancer feed arteries compared to control arteries.
Conclusion: Thinner media and lower alpha(1)-adrenoceptor expression weaken contractions of breast cancer feed arteries in response to sympathetic activity. We propose that abnormalities in breast cancer arteries can be exploited to modify tumor perfusion and thereby either starve cancer cells or facilitate drug and oxygen delivery during chemotherapy or radiotherapy.

• 出版日期2018-3-22