Kumar R, Yarmand-Bagheri R
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Semin Oncol. 2001 Oct;28(5 Suppl 16):27-32. doi: 10.1016/s0093-7754(01)90279-9.
Recent studies have established that growth factors and their receptors play an essential role in regulating the proliferation of epithelial cells. Abnormalities in the expression, structure, or activity of their proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB2 encodes the human epidermal growth factor receptor 2 (HER2), which is overexpressed or amplified or both in several human malignancies including breast, ovarian, and colon cancers. Tumor cells must use the process of vascularization (angiogenesis) for productive growth and metastasis. Overexpression of HER2 in human tumor cells is closely associated with increased angiogenesis and expression of vascular endothelial growth factor (VEGF). Indeed, when the VEGF pathway is inhibited, tumor growth is suppressed. The anti-HER2 blocking antibody trastuzumab has been shown to inhibit tumor cell growth and VEGF expression. Cancer cell invasiveness can be promoted, even in the absence of HER2 overexpression, by transregulation of HER2 by heregulins that bind to HER3 and HER4. Accordingly, heregulin beta1 regulates the expression and secretion of VEGF in breast cancer cells, and trastuzumab inhibits heregulin-mediated angiogenesis both in vitro and in vivo. Thus, potential upregulation of VEGF in cancer epithelial cells likely supports angiogenesis, sustaining and promoting survival and metastasis of tumor cells.
最近的研究证实，生长因子及其受体在调节上皮细胞增殖中起关键作用。其原癌基因产物的表达、结构或活性异常有助于恶性表型的发展和维持。例如，c-erbB2编码人表皮生长因子受体2（HER2），在包括乳腺癌、卵巢癌和结肠癌在内的多种人类恶性肿瘤中，HER2存在过表达、扩增或两者皆有。肿瘤细胞必须利用血管生成过程来实现有效生长和转移。人类肿瘤细胞中HER2的过表达与血管生成增加及血管内皮生长因子（VEGF）的表达密切相关。事实上，当VEGF途径被抑制时，肿瘤生长会受到抑制。抗HER2阻断抗体曲妥珠单抗已被证明可抑制肿瘤细胞生长和VEGF表达。即使在没有HER2过表达的情况下，与HER3和HER4结合的神经调节蛋白对HER2的反式调节也可促进癌细胞的侵袭性。因此，神经调节蛋白β1调节乳腺癌细胞中VEGF的表达和分泌，曲妥珠单抗在体外和体内均可抑制神经调节蛋白介导的血管生成。因此，癌症上皮细胞中VEGF的潜在上调可能支持血管生成，维持并促进肿瘤细胞的存活和转移。
