Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients’ plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as “adhesion competent”. Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer.

高度侵袭性、转移性、神经内分泌前列腺癌通常是由对雄激素剥夺疗法产生耐药性的前列腺癌细胞发展而来，其治疗选择有限，因此预后不良。我们之前已经证明αVβ3整合素在神经内分泌前列腺癌中过度表达。我们现在证明，LM609（一种特异性靶向人类 αVβ3 整合素的单克隆抗体）可在体内阻碍神经内分泌前列腺癌患者来源的异种移植物的生长。我们的研究小组最近发现了一种新型的αVβ3整合素结合伴侣NgR2，它负责调节神经内分泌标志物的表达并诱导前列腺癌细胞的神经内分泌分化。通过体外功能测定，我们证明 NgR2 对于促进细胞与 αVβ3 配体的粘附至关重要。此外，我们首次描述了源自转移性前列腺癌患者血浆的小细胞外囊泡中αVβ3整合素和NgR2的共分离。这些来自前列腺癌患者的小细胞外囊泡对人类单核细胞具有功能影响，增加其与纤连蛋白的粘附。与小细胞外囊泡一起孵育的单核细胞在常规极化标记物表达方面没有显示出相关变化，并且似乎处于可以定义为“粘附能力”的早期阶段。总的来说，这些发现使我们能够更好地了解癌症进展过程中整合素引导的信号传导和细胞间通讯。此外，我们的结果为神经内分泌前列腺癌患者的新诊断和治疗观点铺平了道路。