Data_Sheet_1_Ping-Pong—Tumor and Host in Pancreatic Cancer Progression.PDF

Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.

转移是胰腺癌（PaCa）高死亡率的主要原因，而降低PaCa死亡率的治疗试验并未令人满意。肿瘤的进展主要由肿瘤细胞、尤其是肿瘤起始细胞（CIC）、周围细胞和组织以及远端器官之间的相互作用驱动，其中肿瘤来源的细胞外囊泡（TEX）扮演着至关重要的角色。强烈的间质反应、免疫抑制性白细胞的募集、神经侵犯以及向腹膜腔、肝脏和肺部的早期扩散，这些特征与多种上皮细胞起源的癌症相似，但在PaCa中尤为显著。在此，我们报告了关于PaCIC标志物Tspan8、alpha6beta4、CD44v6、CXCR4、LRP5/6、LRG5、claudin7、EpCAM和CD133的知识现状，这些标志物在转移级联反应的不同阶段均有所参与，通常通过PaCIC-TEX实现。这包括PaCIC标志物对TEX生物发生、靶向和摄取的贡献。随后，我们讨论了PaCa的特异性特征，其中间质成分与肿瘤细胞之间的反馈循环，包括转录异常、信号转导和代谢转变，形成了恶性循环。对于后者，尤其是胰腺星状细胞（PSC）负责，通过代谢转变和直接通过囊泡的营养物质转移来帮助PaCa应对由不良血管生成促进的缺氧。此外，包括Schwann细胞在内的神经细胞传递大量吸引肿瘤细胞的因子，Schwann细胞还通过信号受体结合支持PaCa细胞的存活。PSC、肿瘤相关巨噬细胞和异型间质的成分通过激活包括胆碱能系统在内的信号通路，共同促成神经侵犯。最后，PaCa的侵袭性强烈地受到免疫系统的辅助。尽管免疫细胞丰富，但在肿瘤细胞附近仅恢复免疫抑制性细胞和因子，阻碍效应性免疫细胞进入肿瘤间质。除了免疫刺激因素和受体的缺乏外，免疫抑制性细胞因子、髓源性抑制细胞、调节性T细胞、M2巨噬细胞以及PSC还积极抑制效应细胞的活化。这解释了非适应性免疫系统的NK细胞和适应性免疫系统的细胞毒性T细胞。我们预期进一步解读这些最近揭示的错综复杂的分子背景，将最致命的PaCa转变为可治愈的疾病。