BIOLOGY OF PLASMA CELL TUMOR DEVELOPMENT

人类浆细胞肿瘤最常见的是多发性骨髓瘤，一种无法治愈的癌症。类似的肿瘤也可以在小鼠中由多种试剂诱导，包括油和含致癌基因的逆转录病毒。我们以前已经证明了一些共同的特点与这种疾病在这两个物种。其中包括：1）T细胞在疾病进展中的作用; 2）大多数肿瘤的发展绝对需要白细胞介素-6（IL-6）; 3）肿瘤细胞的骨髓归巢与相关的骨破坏。因此，小鼠系统似乎是一个有用的模型，用于评估与这种形式的瘤形成相关的生化病变以及开发新的治疗方法。我们最近证实了胰岛素样生长因子受体I（IGF-IR）信号通路在浆细胞瘤形成中的作用。发现IGF-IR在油和逆转录病毒（raf/myc）诱导的鼠肿瘤中上调，导致涉及胰岛素应答底物2和磷脂酰肌醇3激酶的下游信号级联的组成性激活。该途径也在由第二种逆转录病毒（abl/myc）诱导的肿瘤中被组成性激活，因此在迄今为止检查的所有浆细胞肿瘤中被解除调节。相反，在一系列B细胞肿瘤中未观察到失调，因此对浆细胞疾病具有特异性。组成性激活途径的生物学相关性已在体外和体内得到证实。最近对一系列骨髓瘤细胞系的研究表明，IGF-IR信号通路在这种疾病的人类形式中也可能是重要的。8个人系中的6个证明了对IGF-I的反应增强了增殖。当动物在肿瘤发展期间接受人IGF-I时，OPM-2系在SCID小鼠中生长更快的能力证明了IGF-I的体内作用。这些结果表明，IGF-I信号通路在人类骨髓瘤中可能发挥重要作用，目前的研究旨在阐明该通路的下游信号元件。IL-6是鼠浆细胞肿瘤发展所绝对需要的，并且在人类中的许多研究类似地表明在骨髓瘤进展中的重要作用。对IL-6通路的研究表明，在受体的下游，Janus激酶1（Jak 1）在随后的信号传导事件中起着关键作用。Jak 1也被鉴定为IL-4信号传导中该家族的关键成员。我们最近已经确定，缺乏Jak 1信号的浆细胞肿瘤有效地通过IL-6和IL-4受体。此外，在存在Jak 1的细胞系中，蛋白质的磷酸化（活化）不会响应于IL-6或IL-4而发生。类似地，没有发现Janus激酶家族的其他已知成员被这些细胞因子激活。这些结果表明，B谱系细胞中的IL-6和IL-4信号传导通过先前未鉴定的中间信号传导分子进行。目前的研究正在进行中，以确定这些目标。该项目以前是Z 01 BC 05553-28 LG -细胞因子，基因治疗，癌基因，浆细胞肿瘤，信号转导，

Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Similar tumors can also be induced in mice by a variety of agents including oils and oncogene containing retroviruses. We have previously demonstrated a number of common features associated with this disease in the two species. These include: 1) a role for T cells in disease progression; 2) an absolute requirement for Interleukin-6 (IL-6) for development of most tumors; 3) bone marrow homing of tumor cells with associated bone destruction. Thus, the murine system appears to be a useful model for both assessing biochemical lesions associated with this form of neoplasia as well as developing new therapeutic approaches. We have recently demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in plasma cell neoplasia. IGF-IR was found to be upregulated in both oil and retroviral (raf/myc) induced murine tumors leading to constitutive activation of a downstream signaling cascade involving Insulin response substrate 2 and phosphatidylinositol 3 kinase. This pathway was also constitutively activated in tumors induced by a second retrovirus (abl/myc) and thus deregulated in all plasma cell tumors examined to date. In contrast, deregulation was not observed in a series of B cell tumors and is thus specific to plasma cell disease. The biological relevance of the constitutively activated pathway has been demonstrated both in vitro and in vivo. Recent studies with a series of myeloma lines suggest that the IGF-IR signaling pathway may also be important in the human form of this disease. Six of eight human lines evidence enhanced proliferation in response to IGF-I. An in vivo role for IGF-I was demonstrated by the ability of the OPM-2 line to grow more rapidly in SCID mice when animals received human IGF-I during the period of tumor development. These results indicate that the IGF-I signaling pathway may play an important role in human myeloma, in general, and current studies are aimed at elucidating the downstream signaling elements in this pathway.A second major pathway involved in plasma cell tumor development involves signaling through the IL-6 receptor. IL-6 is absolutely required for development of murine plasma cell tumors and a number of studies in humans similarly suggest an important role in myeloma progression. Studies of the IL-6 pathway have indicated that, immediately downstream of the receptor, Janus kinase 1 (Jak1) plays a critical role in subsequent signaling events. Jak 1 has also been identified as the critical member of this family in IL-4 signaling. We have recently determined that plasma cell tumors lacking Jak1 signal efficiently through both the IL-6 and IL-4 receptors. Furthermore, in lines in which Jak1 is present, phosphorylation (activation) of the protein does not occur in response to either IL-6 or IL-4. Similarly, no other known members of the Janus kinase family have been found to be activated by these cytokines. These results indicate that IL-6 and IL-4 signaling in B lineage cells proceeds through previously unidentified intermediary signaling molecules. Current studies are underway to identify these targets.This project was formerly Z01 BC 05553-28 LG - Cytokines, gene therapy, Oncogenes, Plasma cell tumors, Signal Transduction,