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認(rèn)為是最難診斷和治療的惡性腫瘤之一。日前，發(fā)表在《自然》雜志上的一項(xiàng)研究發(fā)現(xiàn)，這類癌癥在鄰近腫瘤細(xì)胞的存在下“茁壯成長(zhǎng)”，并且經(jīng)歷著一種特殊形式的細(xì)胞死亡機(jī)制。

通過研究胰腺導(dǎo)管腺癌（pancreatic ductal adenocarcinoma，PDAC）的小鼠模型，紐約大學(xué)的科學(xué)家們發(fā)現(xiàn)，壞死性凋亡（necroptosis）事實(shí)上誘導(dǎo)了驅(qū)動(dòng)PDAC腫瘤細(xì)胞生長(zhǎng)的小蛋白CXCL1的產(chǎn)生。該研究的通訊作者George Miller博士說：“我們的研究首次證明了通過necroptosis調(diào)節(jié)的癌細(xì)胞死亡能夠促進(jìn)腫瘤生長(zhǎng)。同樣重要的是，這一發(fā)現(xiàn)可能也與其它腫瘤類型相關(guān)?！?/p>

CXCL1已知的作用是吸引特異性免疫抑制細(xì)胞、腫瘤相關(guān)巨噬細(xì)胞，它們的功能是降低人類免疫系統(tǒng)識(shí)別和破壞癌細(xì)胞的能力。研究小組進(jìn)一步發(fā)現(xiàn)，僅necroptosis誘導(dǎo)的CXCL1不足以為腫瘤細(xì)胞構(gòu)建保護(hù)環(huán)境。垂死的腫瘤細(xì)胞還會(huì)釋放另一種叫做SAP130的蛋白，該蛋白會(huì)與腫瘤環(huán)境中炎癥性免疫細(xì)胞細(xì)胞膜上的受體Mincle結(jié)合。研究表明，激活Mincle能夠加速小鼠中腫瘤的形成。

科學(xué)家們認(rèn)為，這一研究結(jié)果表明，necroptosis和Mincle信號(hào)通路可以為開發(fā)潛在的抗癌藥提供新的靶點(diǎn)。抑制這些通路能夠逆轉(zhuǎn)免疫抑制，并使抗癌T淋巴細(xì)胞能夠攻擊腫瘤。該研究的共同第一作者Gregor Werba說：“在最初的研究中，抑制PDAC 細(xì)胞中的necroptosis增加了它們?cè)诮M織培養(yǎng)中的生長(zhǎng)能力。然而，當(dāng)相同的方法在小鼠中操作時(shí)，我們驚奇的發(fā)現(xiàn)了相反的結(jié)果，這可能與腫瘤周圍細(xì)胞的免疫響應(yīng)有關(guān)。”

依據(jù)這一結(jié)果，Miller博士和他的團(tuán)隊(duì)正與Perlmutter癌癥中心的Dierdre Cohen博士合作開發(fā)一種抑制necroptosis的化合物單獨(dú)用藥的抗癌潛力，以及與其它免疫療法聯(lián)合用藥的潛能。

癌細(xì)胞“誘騙”健康細(xì)胞

作為最難攻克的惡性腫瘤之一，胰腺導(dǎo)管腺癌似乎有著很多獨(dú)特的“自?！睓C(jī)制。日前，發(fā)表在《細(xì)胞》雜志上的一項(xiàng)研究中，科學(xué)家們發(fā)現(xiàn)，癌細(xì)胞使用突變基因強(qiáng)迫鄰近的健康組織幫助它們生長(zhǎng)和擴(kuò)散。健康細(xì)胞被“誘騙”后釋放獨(dú)特的生長(zhǎng)信號(hào)，癌細(xì)胞借此增殖，但它們本身不能分泌這些信號(hào)。

此前有研究表明，KRAS基因經(jīng)常在癌癥中突變，它的錯(cuò)誤版本對(duì)健康組織有非常重要的影響。這項(xiàng)新研究中科學(xué)家調(diào)查了不同胰腺導(dǎo)管腺癌細(xì)胞中的通訊網(wǎng)絡(luò)，分析了成千上萬種不同的生長(zhǎng)因子、蛋白質(zhì)和受體，發(fā)現(xiàn)了突變KRAS另一項(xiàng)關(guān)鍵的作用，將健康的基質(zhì)細(xì)胞變成癌細(xì)胞的“盟友”。

論文的第一作者Christopher J. Tape博士說：“我們的研究表明，癌細(xì)胞并不是獨(dú)自驅(qū)動(dòng)腫瘤的生長(zhǎng)和擴(kuò)散，還會(huì)誘騙健康的鄰居幫助它們。一些胰腺腫瘤中健康的基質(zhì)細(xì)胞甚至多余癌細(xì)胞。這一結(jié)果為開辟新的療法提供了可能性。”

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

文獻(xiàn)檢索：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.