Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia.

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基质成纤维细胞自噬促进肿瘤结缔组织增生和乳腺肿瘤发生

自噬抑制剂目前正在用于治疗多种癌症的临床试验中进行评估，这主要是因为它们能够阻碍肿瘤细胞存活和代谢适应。最近，人们越来越关注调节宿主基质中的自噬是否以及如何影响肿瘤发生。成纤维细胞在癌症的发生和发展中起着重要作用，包括沉积 1 型胶原蛋白和其他细胞外基质 (ECM) 成分，从而使周围组织变硬以增强肿瘤细胞增殖和存活，以及分泌调节血管生成和免疫微环境的细胞因子。这种表型群在病理学上称为结缔组织增生，预示着预后不良并降低了患者的存活率。使用小鼠乳腺癌模型和同基因移植试验，我们证明，基质成纤维细胞自噬的基因消融显着阻碍了基质促纤维增生反应的基本要素，包括胶原蛋白和促炎细胞因子分泌、细胞外基质硬化和新血管生成。因此，基质成纤维细胞中的自噬对于体内乳腺肿瘤生长是必需的，即使当癌细胞本身保持自噬能力时也是如此。我们提出自噬抑制的功效是由宿主间质成纤维细胞自噬支持肿瘤结缔组织形成的能力决定的。基质成纤维细胞中的自噬是体内乳腺肿瘤生长所必需的，即使当癌细胞本身保持自噬能力时也是如此。我们提出自噬抑制的功效是由宿主间质成纤维细胞自噬支持肿瘤结缔组织形成的能力决定的。基质成纤维细胞中的自噬是体内乳腺肿瘤生长所必需的，即使当癌细胞本身保持自噬能力时也是如此。我们提出自噬抑制的功效是由宿主间质成纤维细胞自噬支持肿瘤结缔组织形成的能力决定的。