Interleukin (IL)-22 is recognized as a tumor-supporting cytokine and is implicated in the proliferation of multiple epithelial cancers. In breast cancer, the current knowledge of IL-22 function is based on cell line models and little is known about how IL-22 affects the tumor initiation, proliferation, invasion, and metastasis in the in vivo system. Here, we investigated the tumor stage-specific function of IL-22 in disease development by evaluating the stage-by-stage progression of breast cancer in an IL-22 knockout spontaneous breast cancer mouse model. We found that among all the stages, IL-22 is specifically upregulated in tumor microenvironment (TME) during the malignant transformation stage of breast tumor progression. The deletion of IL-22 gene leads to the arrest of malignant transition stage, and reduced invasion and tumor burden. Administration of recombinant IL-22 in the TME does not influence in vivo tumor initiation and proliferation but only promotes malignant transformation of cancer cells. Mechanistically, deletion of IL-22 gene causes downregulation of epithelial-to-mesenchymal transition (EMT)-associated transcription factors in breast tumors, suggesting EMT as the mechanism of regulation of malignancy by IL-22. Clinically, in human breast tumor tissues, increased number of IL-22+ cells in the TME is associated with an aggressive phenotype of breast cancer. For the first time, this study provides an insight into the tumor stage-specific function of IL-22 in breast tumorigenesis.

中文翻译：

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白细胞介素22促进自发性乳腺癌小鼠模型中恶性病变的发展。

白介素（IL）-22被认为是一种支持肿瘤的细胞因子，与多种上皮癌的增殖有关。在乳腺癌中，目前对IL-22功能的了解是基于细胞系模型，关于IL-22如何影响体内系统中的肿瘤发生，增殖，侵袭和转移的了解很少。在这里，我们通过评估IL-22基因敲除自发性乳腺癌小鼠模型中乳腺癌的分阶段进展，研究了IL-22在疾病发展中的肿瘤阶段特异性功能。我们发现在所有阶段中，IL-22在乳腺肿瘤进展的恶性转化阶段中在肿瘤微环境（TME）中被特异性上调。IL-22基因的缺失导致恶性过渡期的停止，并减少了侵袭和肿瘤负担。在TME中施用重组IL-22不影响体内肿瘤的发生和增殖，而仅促进癌细胞的恶性转化。从机制上讲，IL-22基因的缺失会导致乳腺肿瘤上皮间质转化（EMT）相关转录因子的下调，提示EMT是IL-22调节恶性肿瘤的机制。临床上，在人类乳腺肿瘤组织中，TME中IL-22 +细胞数量的增加与乳腺癌的侵袭性表型有关。这项研究首次提供了关于IL-22在乳腺肿瘤发生中肿瘤阶段特异性功能的见解。IL-22基因的缺失会导致乳腺肿瘤上皮间质转化（EMT）相关转录因子的下调，提示EMT是IL-22调节恶性肿瘤的机制。临床上，在人类乳腺肿瘤组织中，TME中IL-22 +细胞数量的增加与乳腺癌的侵袭性表型有关。这项研究首次提供了关于IL-22在乳腺肿瘤发生中肿瘤阶段特异性功能的见解。IL-22基因的缺失会导致乳腺肿瘤上皮间质转化（EMT）相关转录因子的下调，提示EMT是IL-22调节恶性肿瘤的机制。临床上，在人类乳腺肿瘤组织中，TME中IL-22 +细胞数量的增加与乳腺癌的侵袭性表型有关。这项研究首次提供了关于IL-22在乳腺肿瘤发生中肿瘤阶段特异性功能的见解。