Gene Expression and Signal Transduction in Transformation and Differentiation

我们研究的主要目标是了解导致分化、细胞生长和肿瘤转化的分子和遗传机制。我们研究了小鼠和人类实验肿瘤系统中的癌基因、肿瘤抑制基因和信号转导蛋白，包括BALB/c小鼠浆细胞瘤、B细胞淋巴瘤和NIH3T3细胞等。这些都是有价值的实验模型，因为它们可以用来为人类多发性骨髓瘤、非霍奇金淋巴瘤和其他人类恶性肿瘤设计更具体的治疗和预防措施。与人类Burkitt淋巴瘤一样，Balb/c浆细胞瘤的特征是原癌基因c-Myc的结构性表达。为了确定完全转化还需要哪些额外的基因改变，我们正在使用全球基因表达的微阵列杂交研究和基于阵列的比较基因组杂交来跟踪从癌前病变到完全恶性浆细胞肿瘤进展过程中的遗传变化和基因表达的变化。我们还利用微阵列杂交研究来探索在小鼠浆细胞肿瘤发展中起作用的分子机制，以及某些转基因和病毒癌基因加速这一肿瘤过程的机制。全球基因表达研究也在进行中，以确定这些肿瘤适应组织培养生长所需的生理变化。我们的假设是，使肿瘤细胞在培养血管的外来环境中生长的这种基因表达的适应性变化，可能类似于人类肿瘤在侵袭或转移后在外来环境中生长所需的变化。作为该项目的延伸，我们观察到在组织培养中生长的小鼠浆细胞肿瘤和在完整动物中生长的相同肿瘤之间的基因表达谱显著不同。我们的研究比较了小鼠和人B细胞淋巴瘤的整体基因表达模式，以及小鼠(浆细胞肿瘤)和人多发性骨髓瘤的浆细胞肿瘤的表达模式，发现不仅B细胞淋巴瘤和浆细胞肿瘤之间，而且人和小鼠浆细胞肿瘤的不同亚型之间也存在显著和特征性的差异。对人类和小鼠浆细胞肿瘤表达模式的非监督等级聚类分析表明，快速出现的小鼠浆细胞肿瘤与临床预后特别差的MM3和MM4多发性骨髓瘤相似。

The chief objective of our research is to understand the molecular and genetic mechanisms responsible for differentiation, cell growth, and neoplastic transformation. We study the oncogenes, tumor-suppressor genes and signal-transducing proteins in mouse and human experimental tumor systems, including BALB/c mouse plasmacytomas, B-cell lymphomas, and NIH 3T3 cells, among others. These are valuable experimental models, because they can be used to devise more specific therapy and preventive measures for human multiple myeloma, non-Hodgkin's lymphomas, and other human malignancies. BALB/c plasmacytomas, like human Burkitt lymphomas, are characterized by constitutive expression of the proto-oncogene, c-Myc. To determine which additional genetic alterations are required for complete transformation, we are using microarray hybridization studies of global gene expression and array-based Comparative Genomic Hybridization to follow genetic changes and changes in gene expression during progression from pre-malignant to fully malignant plasma cell tumors. We are also using microarray hybridization studies to probe the molecular mechanisms at work in development of plasma cell tumors in mice and the mechanisms whereby certain transgenes and viral oncogenes accelerate this neoplastic process. Global gene expression studies are also underway to determine the physiological changes necessary for these tumors to adapt to growth in tissue culture. It is our hypothesis that such adaptive changes in gene expression that enable tumor cells to grow in the foreign environment of culture vessels might be analogous to those needed for human tumors to grow in alien environments following invasion or metastasis. As an extension of this project, we observed marked differences in gene expression profiles between mouse plasma cell tumors growing in tissue culture and the same tumors growing in intact animals. Our studies that compared global gene expression patterns of B-cell lymphomas in mouse and man with expression patterns of plasma cell neoplasms of murine (plasma cell tumors) and human multiple myeloma showed significant and characteriztic differences not only between B-cell lymphomas and plasma cell neoplasms, but also among different subtypes of human and mouse plasma cell neoplasms. Unsupervised hierarchical cluster analysis of expression patterns of the human and murine plasma cell neoplasms showed a similarity between rapid-appearing mouse plasma cell tumors and MM3 and MM4 multiple myelomas, which had particularly poor clinical prognoses.