Department of Biomedicine, University of Bergen, P.O. Box 7804, 5020, Bergen, Norway.
Centre of Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, P.O. Box 7804, 5020, Bergen, Norway.
BMC Cancer. 2019 Mar 15;19(1):234. doi: 10.1186/s12885-019-5449-z.
Cancer progression is influenced by a pro-tumorigenic microenvironment. The aberrant tumor stroma with increased collagen deposition, contractile fibroblasts and dysfunctional vessels has a major impact on the interstitial fluid pressure (PIF) in most solid tumors. An increased tumor PIF is a barrier to the transport of interstitial fluid into and within the tumor. Therefore, understanding the mechanisms that regulate pressure homeostasis can lead to new insight into breast tumor progression, invasion and response to therapy. The collagen binding integrin α11β1 is upregulated during myofibroblast differentiation and expressed on fibroblasts in the tumor stroma. As a collagen organizer and a probable link between contractile fibroblasts and the complex collagen network in tumors, integrin α11β1 could be a potential regulator of tumor PIF.
We investigated the effect of stromal integrin α11-deficiency on pressure homeostasis, collagen organization and tumor growth using orthotopic and ectopic triple-negative breast cancer xenografts (MDA-MB-231 and MDA-MB-468) in wild type and integrin α11-deficient mice. PIF was measured by the wick-in-needle technique, collagen by Picrosirius Red staining and electron microscopy, and uptake of radioactively labeled 5FU by microdialysis. Further, PIF in heterospheroids composed of MDA-MB-231 cells and wild type or integrin α11-deficient fibroblasts was measured by micropuncture.
Stromal integrin α11-deficiency decreased PIF in both the orthotopic breast cancer models. A concomitant perturbed collagen structure was seen, with fewer aligned and thinner fibrils. Integrin α11-deficiency also impeded MDA-MB-231 breast tumor growth, but no effect was observed on drug uptake. No effects were seen in the ectopic model. By investigating the isolated effect of integrin α11-positive fibroblasts on MDA-MB-231 cells in vitro, we provide evidence that PIF regulation was mediated by integrin α11-positive fibroblasts.
We hereby show the importance of integrin α11β1 in pressure homeostasis in triple-negative breast tumors, indicating a new role for integrin α11β1 in the tumor microenvironment. Our data suggest that integrin α11β1 has a pro-tumorigenic effect on triple-negative breast cancer growth in vivo. The significance of the local microenvironment is shown by the different effects of integrin α11β1 in the orthotopic and ectopic models, underlining the importance of choosing an appropriate preclinical model.
肿瘤的进展受到促肿瘤微环境的影响。异常的肿瘤基质伴有胶原沉积增加、收缩性成纤维细胞和功能失调的血管，这对大多数实体瘤中的间质液压力（PIF）有重大影响。肿瘤 PIF 的增加是间质液向肿瘤内和肿瘤内运输的障碍。因此，了解调节压力平衡的机制可以为乳腺癌的进展、浸润和对治疗的反应提供新的见解。在肌成纤维细胞分化过程中，胶原结合整合素α11β1上调，并在肿瘤基质的成纤维细胞上表达。作为胶原组织者和肿瘤中收缩性成纤维细胞与复杂胶原网络之间的可能联系，整合素α11β1可能是肿瘤 PIF 的潜在调节剂。
我们使用野生型和整合素α11缺陷型小鼠中的原位和异位三阴性乳腺癌异种移植（MDA-MB-231 和 MDA-MB-468），研究基质整合素α11缺陷对压力平衡、胶原组织和肿瘤生长的影响。通过 Wick-in-Needle 技术测量 PIF，用 Picrosirius Red 染色和电子显微镜测量胶原，用微透析测量放射性标记的 5FU 的摄取。此外，通过微穿刺测量由 MDA-MB-231 细胞和野生型或整合素α11缺陷型成纤维细胞组成的异质球体中的 PIF。
基质整合素α11缺陷降低了两种原位乳腺癌模型中的 PIF。胶原结构也出现了紊乱，纤维排列更稀疏，更细。整合素α11缺陷也阻碍了 MDA-MB-231 乳腺癌的生长，但对药物摄取没有影响。在异位模型中没有观察到这种影响。通过研究整合素α11阳性成纤维细胞对 MDA-MB-231 细胞的体外的单独影响，我们提供了证据表明，PIF 的调节是由整合素α11阳性成纤维细胞介导的。
我们在此表明整合素α11β1在三阴性乳腺癌中的压力平衡中的重要性，这表明整合素α11β1在肿瘤微环境中有新的作用。我们的数据表明，整合素α11β1对三阴性乳腺癌在体内的生长具有促肿瘤作用。局部微环境的重要性体现在整合素α11β1在原位和异位模型中的不同作用上，这强调了选择合适的临床前模型的重要性。
