Human PDAC tumors shows co-expression of CXCL1 (red) and CK19 (green; a marker of PADC) by confocal microscopy.
最具侵略性的胰腺癌通常被认为是最难诊断和治疗的恶性肿瘤之一。日前，发表在《自然》杂志上的一项研究发现，这类癌症在邻近肿瘤细胞的存在下“茁壮成长”，并且经历着一种特殊形式的细胞死亡机制。
通过研究胰腺导管腺癌（pancreatic ductal adenocarcinoma，PDAC）的小鼠模型，纽约大学的科学家们发现，坏死性凋亡（necroptosis）事实上诱导了驱动PDAC肿瘤细胞生长的小蛋白CXCL1的产生。该研究的通讯作者George Miller博士说：“我们的研究首次证明了通过necroptosis调节的癌细胞死亡能够促进肿瘤生长。同样重要的是，这一发现可能也与其它肿瘤类型相关。”
CXCL1已知的作用是吸引特异性免疫抑制细胞、肿瘤相关巨噬细胞，它们的功能是降低人类免疫系统识别和破坏癌细胞的能力。研究小组进一步发现，仅necroptosis诱导的CXCL1不足以为肿瘤细胞构建保护环境。垂死的肿瘤细胞还会释放另一种叫做SAP130的蛋白，该蛋白会与肿瘤环境中炎症性免疫细胞细胞膜上的受体Mincle结合。研究表明，激活Mincle能够加速小鼠中肿瘤的形成。
科学家们认为，这一研究结果表明，necroptosis和Mincle信号通路可以为开发潜在的抗癌药提供新的靶点。抑制这些通路能够逆转免疫抑制，并使抗癌T淋巴细胞能够攻击肿瘤。该研究的共同第一作者Gregor Werba说：“在最初的研究中，抑制PDAC 细胞中的necroptosis增加了它们在组织培养中的生长能力。然而，当相同的方法在小鼠中操作时，我们惊奇的发现了相反的结果，这可能与肿瘤周围细胞的免疫响应有关。”
依据这一结果，Miller博士和他的团队正与Perlmutter癌症中心的Dierdre Cohen博士合作开发一种抑制necroptosis的化合物单独用药的抗癌潜力，以及与其它免疫疗法联合用药的潜能。
癌细胞“诱骗”健康细胞
作为最难攻克的恶性肿瘤之一，胰腺导管腺癌似乎有着很多独特的“自保”机制。日前，发表在《细胞》杂志上的一项研究中，科学家们发现，癌细胞使用突变基因强迫邻近的健康组织帮助它们生长和扩散。健康细胞被“诱骗”后释放独特的生长信号，癌细胞借此增殖，但它们本身不能分泌这些信号。
此前有研究表明，KRAS基因经常在癌症中突变，它的错误版本对健康组织有非常重要的影响。这项新研究中科学家调查了不同胰腺导管腺癌细胞中的通讯网络，分析了成千上万种不同的生长因子、蛋白质和受体，发现了突变KRAS另一项关键的作用，将健康的基质细胞变成癌细胞的“盟友”。
论文的第一作者Christopher J. Tape博士说：“我们的研究表明，癌细胞并不是独自驱动肿瘤的生长和扩散，还会诱骗健康的邻居帮助它们。一些胰腺肿瘤中健康的基质细胞甚至多余癌细胞。这一结果为开辟新的疗法提供了可能性。”
文献检索：doi:10.1038/nature17403
Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis1. Conversely, cancer cells often disrupt apoptosis to survive2, 3. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs4, 5. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle—its cognate receptor—was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
来源：生物探索
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