B-cell-derived lymphotoxin promotes castration-resistant prostate cancer.
B-cell-derived lymphotoxin promotes castration-resistant prostate cancer.
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前列腺癌（CaP）从前列腺上皮内瘤变经局部浸润性腺癌发展为去势抵抗性（CR）转移癌。虽然根治性前列腺切除术、放疗和雄激素消融术是雄激素依赖性（AD）CaP的有效治疗方法，但转移性CR-CaP是一种死亡率高的主要并发症。雄激素刺激前列腺上皮和早期CaP的生长和存活。虽然大多数患者最初对雄激素消融有反应，但许多患者在12-18个月内发展为CR-CaP。尽管进行了广泛的研究，但CR-CaP出现的机制仍然知之甚少，其阐明对于开发改进的疗法至关重要。奇怪的是，CR-CaP仍然是雄激素受体（AR）依赖性的，而有效的AR拮抗剂在去势小鼠中诱导肿瘤消退。炎症在CR-CaP中的作用尚未得到解决，尽管有报道称内在NF-κB活化支持其生长。炎症是对损伤或感染的局部保护性反应，但它在许多疾病（包括癌症）中也具有致病作用。急性炎症对于宿主防御至关重要，而慢性炎症有助于肿瘤发生和转移进展。炎症反应性IκB激酶（IKK）β及其靶点NF-κB在恶性细胞和炎症细胞中具有重要的促肿瘤作用。后者，包括巨噬细胞和淋巴细胞，是肿瘤微环境的重要组成部分，但其募集的机制仍然不清楚，尽管被认为取决于趋化因子和细胞因子的产生。我们发现CaP进展与炎症浸润和IKKα激活有关，IKKα通过NF-κ B非依赖性、细胞自主性机制刺激转移。我们现在发现，雄激素去除可导致退行性AD肿瘤浸润白细胞，包括B细胞，其中IKKβ激活导致细胞因子的产生，这些细胞因子激活CaP细胞中的IKKα和STAT 3，以提高无瘤生存率。
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration resistant (CR) metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent (AD) CaP, metastatic CR-CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop CR-CaP within 12-18 months. Despite extensive studies, the mechanisms underlying CR-CaP emergence remain poorly understood and their elucidation is critical for development of improved therapies. Curiously, CR-CaP remains androgen receptor (AR) dependent and potent AR antagonists induce tumor regression in castrated mice. The role of inflammation in CR-CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defense, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK) β and its target NF-κB have important tumor promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumor microenvironment, but the mechanisms underlying their recruitment remain obscure, although thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKKα, which stimulates metastasis by an NF-κB-independent, cell autonomous, mechanism. We now show that androgen ablation causes infiltration of regressing AD tumors with leukocytes, including B cells, in which IKKβ activation results in production of cytokines that activate IKKα and STAT3 in CaP cells to enhance hormone-free survival.
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