Nicolson G L, Moustafa A S
Institute for Molecular Medicine, Huntington Beach, CA 92649, USA.
In Vivo. 1998 Nov-Dec;12(6):579-88.
The morbidity in most cancer patients is not due to their primary cancers; it is due to metastatic disease. Thus understanding the progression of tumors to the metastatic state and the changes that take place in highly malignant cells are important in the development of new therapeutic approaches to diagnose, prognostically assess and treat highly progressive malignancies. Changes in the expression of certain genes or alterations of gene structures and encoded products can result in benign tumor cells progressing to the invasive and metastatic states. This has been shown in the laboratory by transferring dominantly acting oncogenes into susceptible cells and then testing the malignant properties of these cells in vivo. Usually such rapid qualitative changes in malignant state occur only rarely; the natural progression of tumor cells to the invasive or metastatic state occurs through a slow stepwise process of change. Tumor progression, in some instances, can be reversible, involving changes in dominantly acting oncogenes or tumor suppressor genes. The natural progression of tumors to highly malignant states also involves their ability to circumvent host microenvironmental controls that regulate cellular growth and diversity. Quantitative changes in gene expression rather than qualitative changes in gene structure are important in microenvironmental effects on progression. One of the important mechanisms of cellular regulation in epithelial tissues, such as breast epithelium, appears to be mediated by intercellular junctional communication. Changes in gene expression can result in loss of junctional communication, followed by cellular diversification and progression. Highly malignant tumor cells that have slowly evolved in vivo with only a few qualitative changes in gene structure have probably undergone extensive cycles of diversification and have multiple quantitative differences in gene expression. Some of these genes are related to metastasis. For example, we have identified a novel gene called mta1 (rat) or MTA1 (human) that appears to be involved in mammary cell motility and growth regulation. This may be an example of a gene that regulates highly malignant cellular phenotypes. When coupled with other cellular changes, such as loss of intercellular communication, specific changes in gene expression may result in cellular diversification and tumor progression.
大多数癌症患者的发病并非源于其原发性癌症，而是由于转移性疾病。因此，了解肿瘤向转移状态的进展以及高恶性细胞中发生的变化，对于开发诊断、预后评估和治疗高度进展性恶性肿瘤的新治疗方法至关重要。某些基因表达的变化或基因结构及编码产物的改变可导致良性肿瘤细胞进展为侵袭性和转移性状态。这已在实验室中通过将显性作用的癌基因导入易感细胞，然后在体内测试这些细胞的恶性特性得到证实。通常，恶性状态的这种快速定性变化很少发生；肿瘤细胞向侵袭性或转移性状态的自然进展是通过缓慢的逐步变化过程发生的。在某些情况下，肿瘤进展可能是可逆的，涉及显性作用癌基因或肿瘤抑制基因的变化。肿瘤向高度恶性状态的自然进展还涉及它们规避调节细胞生长和多样性的宿主微环境控制的能力。基因表达的定量变化而非基因结构的定性变化在微环境对进展的影响中很重要。上皮组织（如乳腺上皮）中细胞调节的重要机制之一似乎是由细胞间连接通讯介导的。基因表达的变化可导致连接通讯丧失，随后是细胞多样化和进展。在体内缓慢进化、基因结构仅有少数定性变化的高度恶性肿瘤细胞可能经历了广泛的多样化循环，并且在基因表达上有多个定量差异。其中一些基因与转移有关。例如，我们已经鉴定出一种名为mta1（大鼠）或MTA1（人类）的新基因，它似乎参与乳腺细胞运动和生长调节。这可能是一个调节高度恶性细胞表型的基因的例子。当与其他细胞变化（如细胞间通讯丧失）相结合时，基因表达的特定变化可能导致细胞多样化和肿瘤进展。
