Murine breast cancer feed arteries are thin-walled with reduced α1A-adrenoceptor expression and attenuated sympathetic vasocontraction

Abstract

BackgroundPerfusion 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.MethodsWe 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 α1-adrenoceptor antagonist prazosin.ResultsBreast 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 α1-adrenoceptors and messenger RNA levels for α1A-adrenoceptors are lower in breast cancer arteries than control arteries. Sympathetic vasocontraction elicited by electrical field stimulation is inhibited by α1-adrenoceptor blockade and reduced in breast cancer feed arteries compared to control arteries.ConclusionThinner media and lower α1-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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0952-8) contains supplementary material, which is available to authorized users.

Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries

“…The overall conclusion from the present study, that cancer feed arteries are specialized toward reduced vascular resistance, is in agreement with a recent study on murine breast cancer feed arteries (12). The underlying cellular and molecular mechanisms that explain the lower vascular tone of cancer feed arteries compared with normal arteries, however, differ greatly between human colon cancer and murine breast cancer.…”

“…The underlying cellular and molecular mechanisms that explain the lower vascular tone of cancer feed arteries compared with normal arteries, however, differ greatly between human colon cancer and murine breast cancer. Feed arteries from murine breast cancer tissue induced by overexpression of receptor tyrosine protein kinase erbB-2 are thin walled and show substantial reduction in norepinephrineinduced contractions and ␣ 1A -adrenoceptor expression but no difference in endothelial function (12). It is yet unknown whether the dissimilarities between murine breast cancer feed arteries and human colon cancer feed arteries result from differences in species, in the vascular bed, or in the secretory or metabolic activity of breast and colon cancer tissue.…”

The Acidic Tumor Microenvironment as a Driver of Cancer

“…The formation of new blood vessels (i.e., angiogenesis) and incorporation of existing blood vessels from surrounding tissue (i.e., co-option) partially counteract the diffusion limitations (120). As discussed in greater detail below, the tumor blood vessels may also undergo functional adaptations that promote blood flow delivery to the cancer tissue (121,122). In fact, blood flow delivery to some tumor regions can be substantially higher than to corresponding normal tissue (123), although O 2 delivery usually remains insufficient to match the elevated metabolic demand.…”

“…As a consequence, extratumoral blood vessels contribute substantially to tumor vascular resistance, and changes in the contractile state of tumor feed arteries are expected to significantly modify tumor blood flow. Murine breast cancer feed arteries and human colon cancer feed arteries show functional specialization that facilitates vasodilation or inhibits vasocontraction (121,122) and thereby minimizes vascular resistance compared to corresponding normal arteries. The mechanisms explaining the reduced vascular resistance of cancer feed arteries depend on the source of the arteries.…”

Promoter aberrant methylation status ofADRA1Ais associated with hepatocellular carcinoma

“…ADRA1A, as a subtype of the alpha ARs, is activated by catecholamines from local sympathetic nerve fibres and circulating blood. Lower α1-AR expression in breast cancer feed arteries was detected in a previous study, and this lowered receptor expression could increase tumour perfusion and provide more nutrients for the cancer cells by decreasing feed artery constriction [19]. ADRA1A is the predominant subtype of α1-AR in the normal liver [20].…”