Walch E T, Albino A P, Marchetti D
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Int J Cancer. 1999 Jul 2;82(1):112-20. doi: 10.1002/(sici)1097-0215(19990702)82:1<112::aid-ijc19>3.0.co;2-9.
The role of growth factor receptors in regulating the progression of human melanocytes toward tumorigenicity and ultimately a malignant phenotype is poorly understood. In particular, the autocrine and paracrine influences that modulate cellular invasion and extracellular matrix (ECM)-degradative enzymes in melanoma cells remain undefined at the molecular level. The low-affinity p75 neurotrophin receptor (p75NTR), a cysteine-rich transmembrane glycoprotein, is frequently expressed in advanced stages of human melanoma, but the biological consequences of this expression are unknown. p75NTR can enhance the invasive potential of brain-metastatic melanoma cells in vitro. We have extended here these results and related the level of p75NTR in human metastatic melanoma cells to their invasive potential to target organs other than brain. Fluorescence activated cell sorting (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W) had differential p75NTR contents, whereas SK-MEL-147 cells had elevated amounts of p75NTR. Two other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point mutations in the p75NTR transmembrane domain had reduced (SK-MEL-94) or absent (SK-MEL-110) p75NTR. We also examined these cell lines for presence of TrkA receptor, the high-affinity receptor for nerve growth factor (NGF), the prototypic neurotrophin. No TrkA receptor expression was detected in any of the cell lines. The extent of p75NTR expression correlated with the capability of NGF to promote cellular invasion and with production of heparanase, an important ECM-degradative enzyme. Melanoma cells sorted for high p75NTR expression (p75NTR-H cells) had markedly greater (9- to 13-fold increase) invasive capabilities in response to NGF exposure than those sorted for low p75NTR expression (p75NTR-L cells). Additionally, NGF induced a 8- to 10-fold increase of heparanase activity in p75NTR-H cells. Thus, we propose that p75NTR-mediated trophic support profoundly affects melanoma cell invasion to neurotrophin-rich organs.
生长因子受体在调节人类黑素细胞向致瘤性进而向恶性表型发展过程中的作用尚不清楚。特别是，在分子水平上，调节黑素瘤细胞中细胞侵袭和细胞外基质（ECM）降解酶的自分泌和旁分泌影响仍不明确。低亲和力p75神经营养因子受体（p75NTR）是一种富含半胱氨酸的跨膜糖蛋白，在人类黑素瘤晚期经常表达，但其表达的生物学后果尚不清楚。p75NTR可增强脑转移性黑素瘤细胞在体外的侵袭潜能。我们在此扩展了这些结果，并将人类转移性黑素瘤细胞中p75NTR的水平与其对脑以外靶器官的侵袭潜能联系起来。荧光激活细胞分选（FACS）分析显示，3种黑素瘤细胞系（SK-MEL-146、SK-MEL-119、70W）的p75NTR含量不同，而SK-MEL-147细胞的p75NTR含量升高。另外两种在p75NTR跨膜结构域存在点突变的黑素瘤细胞系（SK-MEL-94、SK-MEL-110），p75NTR减少（SK-MEL-94）或缺失（SK-MEL-110）。我们还检测了这些细胞系中神经生长因子（NGF）的高亲和力受体TrkA受体的存在情况。在任何细胞系中均未检测到TrkA受体表达。p75NTR的表达程度与NGF促进细胞侵袭的能力以及硫酸乙酰肝素酶（一种重要的ECM降解酶）的产生相关。分选得到的高p75NTR表达黑素瘤细胞（p75NTR-H细胞）在暴露于NGF时的侵袭能力比分选得到的低p75NTR表达细胞（p75NTR-L细胞）显著增强（增加9至13倍）。此外，NGF诱导p75NTR-H细胞中硫酸乙酰肝素酶活性增加8至10倍。因此，我们提出p75NTR介导的营养支持深刻影响黑素瘤细胞向富含神经营养因子的器官的侵袭。
