Bissell M J, Weaver V M, Lelièvre S A, Wang F, Petersen O W, Schmeichel K L
Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Cancer Res. 1999 Apr 1;59(7 Suppl):1757-1763s; discussion 1763s-1764s.
Because every cell within the body has the same genetic information, a significant problem in biology is to understand how cells within a tissue express genes selectively. A sophisticated network of physical and biochemical signals converge in a highly orchestrated manner to bring about the exquisite regulation that governs gene expression in diverse tissues. Thus, the ultimate decision of a cell to proliferate, express tissue-specific genes, or apoptose must be a coordinated response to its adhesive, growth factor, and hormonal milieu. The unifying hypothesis examined in this overview is that the unit of function in higher organisms is neither the genome nor the cell alone but the complex, three-dimensional tissue. This is because there are bidirectional connections between the components of the cellular microenvironment (growth factors, hormones, and extracellular matrix) and the nucleus. These connections are made via membrane-bound receptors and transmitted to the nucleus, where the signals result in modifications to the nuclear matrix and chromatin structure and lead to selective gene expression. Thus, cells need to be studied "in context", i.e., within a proper tissue structure, if one is to understand the bidirectional pathways that connect the cellular microenvironment and the genome. In the last decades, we have used well-characterized human and mouse mammary cell lines in "designer microenvironments" to create an appropriate context to study tissue-specific gene expression. The use of a three-dimensional culture assay, developed with reconstituted basement membrane, has allowed us to distinguish normal and malignant human breast cells easily and rapidly. Whereas normal cells become growth arrested and form organized "acini," tumor cells continue to grow, pile up, and in general fail to respond to extracellular matrix and microenvironmental cues. By correcting the extracellular matrix-receptor (integrin) signaling and balance, we have been able to revert the malignant phenotype when a human breast tumor cell is cultured in, or on, a basement membrane. Most recently, we have shown that whereas beta1 integrin and epidermal growth factor receptor signal transduction pathways are integrated reciprocally in three-dimensional cultures, on tissue culture plastic (two-dimensional monolayers), these are not coordinated. Finally, we have demonstrated that, rather than passively reflecting changes in gene expression, nuclear organization itself can modulate cellular and tissue phenotype. We conclude that the structure of the tissue is dominant over the genome, and that we may need a new paradigm for how epithelial-specific genes are regulated in vivo. We also argue that unless the structure of the tissue is critically altered, malignancy will not progress, even in the presence of multiple chromosomal mutations.
由于体内的每个细胞都具有相同的遗传信息，生物学中的一个重大问题是了解组织内的细胞如何选择性地表达基因。一个复杂的物理和生化信号网络以高度协调的方式汇聚在一起，以实现对不同组织中基因表达的精确调控。因此，细胞增殖、表达组织特异性基因或凋亡的最终决定必须是对其黏附、生长因子和激素环境的协调反应。本综述探讨的统一假设是，高等生物中的功能单位既不是基因组也不是单个细胞，而是复杂的三维组织。这是因为细胞微环境的组成部分（生长因子、激素和细胞外基质）与细胞核之间存在双向连接。这些连接通过膜结合受体建立并传递到细胞核，在那里信号导致核基质和染色质结构发生改变，并导致选择性基因表达。因此，如果要了解连接细胞微环境和基因组的双向途径，就需要在适当的组织结构中“在特定环境下”研究细胞。在过去几十年中，我们在“设计微环境”中使用了特征明确的人和小鼠乳腺细胞系，以创造一个合适的环境来研究组织特异性基因表达。使用由重组基底膜开发的三维培养测定法，使我们能够轻松快速地区分正常和恶性人乳腺细胞。正常细胞会停止生长并形成有组织的“腺泡”，而肿瘤细胞则继续生长、堆积，并且通常对细胞外基质和微环境信号无反应。通过纠正细胞外基质-受体（整合素）信号传导和平衡，当人乳腺肿瘤细胞在基底膜中或在基底膜上培养时，我们能够逆转其恶性表型。最近，我们发现，虽然β1整合素和表皮生长因子受体信号转导途径在三维培养中相互整合，但在组织培养塑料（二维单层）上，它们并不协调。最后，我们证明，核组织本身并非被动反映基因表达的变化，而是可以调节细胞和组织表型。我们得出结论，组织的结构比基因组更具主导性，并且我们可能需要一个新的范式来解释上皮特异性基因在体内是如何被调控的。我们还认为，除非组织的结构发生严重改变，否则即使存在多个染色体突变，恶性肿瘤也不会进展。
