Bencze Noémi, Schvarcz Csaba, Kriszta Gábor, Danics Lea, Szőke Éva, Balogh Péter, Szállási Árpád, Hamar Péter, Helyes Zsuzsanna, Botz Bálint
Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.
János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.
Front Oncol. 2021 Jul 14;11:685297. doi: 10.3389/fonc.2021.685297. eCollection 2021.
There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer. The ultrapotent capsaicin-analogue resiniferatoxin (RTX) was used for the selective, systemic desensitization of capsaicin-sensitive afferents. Growth and viability of orthotopically implanted 4T1 tumors were measured by caliper, MRI, and bioluminescence imaging, while tumor vascularity and protease enzyme activity were assessed using fluorescent imaging. The levels of the neuropeptides Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), and somatostatin were measured from tumor tissue homogenates using radioimmunoassay, while tumor structure and peritumoral inflammation were evaluated by conventional use of CD31, CD45 and CD3 immunohistology. RTX-pretreated mice demonstrated facilitated tumor growth in the early phase measured using a caliper, which was coupled with increased tumor vascular leakage demonstrated using fluorescent vascular imaging. The tumor size difference dissipated by day seven. The MRI tumor volume was similar, while the intratumoral protease enzyme activity measured by fluorescence imaging was also comparable in RTX-pretreated and non-pretreated animals. Tumor viability or immunohistopathological profile was measured using CD3, CD31, and CD45 stains and did not differ significantly from the non-pretreated control group. Intratumoral somatostatin, CGRP, and SP levels were similar in both groups. Our results underscore the beneficial, antitumoral properties of capsaicin sensitive nerve terminals in this aggressive model of breast cancer, which is presumed to be due to the inhibition of tumor vascular bed disruption. The absence of any difference in intratumoral neuropeptide levels indicates non-neural sources playing a substantial part in their expression.
神经驱动机制在肿瘤发生和肿瘤生长中的作用正受到越来越多的关注。先前已表明，对辣椒素敏感的传入神经具有抗肿瘤和免疫调节特性，但其机制目前尚不清楚。在本研究中，我们评估了这些神经末梢在三阴性4T1原位乳腺癌小鼠模型中的作用。使用超效辣椒素类似物树脂毒素（RTX）对辣椒素敏感的传入神经进行选择性全身脱敏。通过卡尺、磁共振成像（MRI）和生物发光成像测量原位植入的4T1肿瘤的生长和活力，同时使用荧光成像评估肿瘤血管生成和蛋白酶活性。使用放射免疫分析法从肿瘤组织匀浆中测量神经肽降钙素基因相关肽（CGRP）、P物质（SP）和生长抑素的水平，同时通过常规使用CD31、CD45和CD3免疫组织学评估肿瘤结构和肿瘤周围炎症。RTX预处理的小鼠在早期使用卡尺测量显示肿瘤生长加快，同时荧光血管成像显示肿瘤血管渗漏增加。到第7天时，肿瘤大小差异消失。MRI测量的肿瘤体积相似，同时荧光成像测量的肿瘤内蛋白酶活性在RTX预处理和未预处理的动物中也相当。使用CD3、CD31和CD45染色测量肿瘤活力或免疫组织病理学特征，与未预处理的对照组相比无显著差异。两组肿瘤内生长抑素、CGRP和SP水平相似。我们的结果强调了在这种侵袭性乳腺癌模型中，辣椒素敏感神经末梢具有有益的抗肿瘤特性，推测这是由于抑制了肿瘤血管床破坏。肿瘤内神经肽水平没有任何差异，表明非神经来源在其表达中起重要作用。
