Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix.
Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix.
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DOI：
10.1101/gad.249599.114
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发表时间：
2014-10-01
影响因子：
10.5
通讯作者：
Joyce JA
中科院分区：
文献类型：
--
作者：
Akkari L;Gocheva V;Kester JC;Hunter KE;Quick ML;Sevenich L;Wang HW;Peters C;Tang LH;Klimstra DS;Reinheckel T;Joyce JA
Akkari等人。研究了由癌细胞和巨噬细胞提供的组织蛋白酶Z(CtsZ)在胰腺神经内分泌肿瘤中的作用。肿瘤的增殖完全由癌细胞固有的CtsZ功能调控，而肿瘤的侵袭则需要巨噬细胞和癌细胞的共同作用。这些结果强调了肿瘤微环境中相互作用的复杂性，并表明细胞来源可以影响分子功能。在肿瘤的发展过程中，癌细胞可以产生必要的生长和侵袭促进因子，也可以依赖肿瘤微环境中的非肿瘤细胞作为替代的细胞外源。然而，细胞来源是否影响这些促肿瘤因子的功能仍然是一个悬而未决的问题。在这里，我们研究了由癌细胞和巨噬细胞提供的组织蛋白酶Z(CtsZ)在人类和小鼠胰腺神经内分泌肿瘤中的作用。我们发现，肿瘤的增殖完全由肿瘤细胞固有的CtsZ功能调节，而肿瘤的侵袭需要巨噬细胞和癌细胞的共同作用。有趣的是，CtsZ的一些促肿瘤功能并不依赖于其所描述的催化活性，而是通过酶原结构域中的Arg-Gly-Asp(RGD)基序介导的，该基序调节与整合素和细胞外基质的相互作用。总之，这些结果强调了肿瘤微环境中相互作用的复杂性，并表明细胞来源确实可以影响分子功能。
Akkari et al. examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors. Tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. These results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can impact molecular function. During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.
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影响因子：
9.2
作者：
Byron, Adam;Morgan, Mark R.;Humphries, Martin J.
通讯作者：
Humphries, Martin J.
影响因子：
3.7
作者：
Gocheva V;Chen X;Peters C;Reinheckel T;Joyce JA
通讯作者：
Joyce JA
影响因子：
8
作者：
Fisher, GH;Orsulic, S;Varmus, HE
通讯作者：
Varmus, HE
影响因子：
4
作者：
Humphries JD;Byron A;Humphries MJ
通讯作者：
Humphries MJ
影响因子：
4
作者：
Jevnikar, Zala;Obermajer, Natasa;Kos, Janko
通讯作者：
Kos, Janko