Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.
Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.
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乳腺癌细胞产生的自分泌运动因子数量极少。我们假设，与乳腺肿瘤相邻的发炎乳腺脂肪细胞所产生的自分泌运动因子是自分泌运动因子分泌的一个主要来源，它驱动乳腺肿瘤进展以及治疗效果的丧失。我们通过使用脂肪细胞特异性敲除自分泌运动因子的小鼠来验证这一假设。这种敲除并没有降低同基因C57BL/6小鼠中E0771肿瘤的生长，也没有降低MMTV - PyMT小鼠中自发性乳腺肿瘤的生长和肺转移。尽管如此，用IOA - 289抑制自分泌运动因子降低了小鼠中E0771肿瘤的生长。这表明除脂肪细胞外的其他细胞对促进乳腺肿瘤生长负有责任。
乳腺癌细胞产生的自分泌运动因子数量极少。相反，先前的研究表明，与乳腺肿瘤相邻的发炎脂肪组织中的脂肪细胞是自分泌运动因子分泌的一个主要来源，它驱动乳腺肿瘤生长、转移以及化疗和放疗效果的丧失。为了验证这一假设，我们使用了脂肪细胞特异性敲除自分泌运动因子的小鼠。脂肪细胞缺乏自分泌运动因子分泌并没有降低同基因C57BL/6小鼠中原位E0771乳腺肿瘤的生长，也没有降低MMTV - PyMT小鼠中自发性乳腺肿瘤的生长和肺转移。然而，用IOA - 289抑制自分泌运动因子降低了E0771肿瘤的生长，这表明自分泌运动因子的另一个来源对肿瘤生长负有责任。肿瘤相关成纤维细胞和白细胞在E0771乳腺肿瘤中产生大部分自分泌运动因子转录本，我们假设它们是驱动乳腺肿瘤生长的自分泌运动因子的主要来源。用IOA - 289抑制自分泌运动因子增加了肿瘤中CD8α⁺ - T细胞的数量。与此同时，血浆中CXCL10、CCL2和CXCL9的浓度以及肿瘤中LIF、TGFβ1、TGFβ2和催乳素的浓度降低。对人类乳腺肿瘤数据库的生物信息学分析表明，自分泌运动因子（ENPP2）主要在内皮细胞和成纤维细胞中表达。自分泌运动因子的表达与IL - 6细胞因子受体配体相互作用的增加、LIF、TGFβ和催乳素的信号传导显著相关。这证实了小鼠模型中自分泌运动因子抑制结果的相关性。我们提出，抑制来自呈现乳腺肿瘤的细胞（如成纤维细胞、白细胞或内皮细胞）的自分泌运动因子活性，会改变肿瘤微环境，从而抑制肿瘤生长。
Breast cancer cells produce negligible quantities of autotaxin. We hypothesized that the autotaxin produced by inflamed breast adipocytes adjacent to breast tumors provides a major source of autotaxin secretion that drives breast tumor progression and the loss of treatment efficacy. We tested this hypothesis by using mice with an adipocyte-specific knock out of autotaxin. This knockout did not decrease the growth of E0771 tumors in syngeneic C57BL/6 mice or the growth and lung metastasis of spontaneous breast tumors in MMTV-PyMT mice. Despite this, the inhibition of autotaxin with IOA-289 decreased the growth of E0771 tumors in the mice. This demonstrates that cells other than adipocytes are responsible for promoting breast tumor growth. Breast cancer cells produce negligible quantities of autotaxin. Instead, previous work indicated that adipocytes in the inflamed adipose tissue adjacent to breast tumors are a major source of autotaxin secretion that drives breast tumor growth, metastasis, and the loss of efficacy for chemotherapy and radiotherapy. To test this hypothesis, we used mice with an adipocyte-specific knock out of autotaxin. The lack of autotaxin secretion from adipocytes failed to decrease the growth of orthotopic E0771 breast tumors in syngeneic C57BL/6 mice and the growth and lung metastasis of spontaneous breast tumors in MMTV-PyMT mice. However, the inhibition of autotaxin with IOA-289 decreased the growth of E0771 tumors, indicating that another source of autotaxin is responsible for tumor growth. Tumor-associated fibroblasts and leukocytes produce the majority of autotoxin transcripts in the E0771 breast tumors, and we hypothesize that they are the main sources of ATX that drive breast tumor growth. Autotaxin inhibition with IOA-289 increased the numbers of CD8α+-T-cells in the tumors. This was accompanied by decreases in the concentrations of CXCL10, CCL2, and CXCL9 in the plasma and LIF, TGFβ1, TGFβ2, and prolactin in the tumors. Bioinformatics analysis of human breast tumor databases showed that autotaxin (ENPP2) is expressed mainly in endothelial cells and fibroblasts. Autotaxin expression correlated significantly with increases in IL-6 cytokine receptor ligand interactions, signaling by LIF, TGFβ, and prolactin. This confirms the relevance of results from autotaxin inhibition in the mouse model. We propose that inhibiting autotaxin activity that is derived from cells presenting breast tumors such as fibroblasts, leukocytes, or endothelial cells changes the tumor micro-environment in such a way as to inhibit tumor growth.
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