Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human-melanoma brain metastases.
Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human-melanoma brain metastases.
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人黑色素瘤脑转移侵袭前沿神经营养因子和神经营养因子受体的逆表达。
DOI：
10.3892/ijo.7.1.87
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发表时间：
1995
影响因子：
5.2
通讯作者：
Garth L. Nicolson
中科院分区：
文献类型：
--
作者：
Dario Marchetti;I.E. McCutcheon;M. Ross;Garth L. Nicolson
神经营养因子（NT），如神经生长因子（NGF），刺激几个神经元亚群的生长和分化，在一个独特的但重叠的方式。脑转移性人黑色素瘤细胞过表达p75（NTR）（低亲和力神经营养因子受体），并且用NGF处理脑转移性细胞刺激细胞外基质侵袭和与p75（NTR）的细胞表达相关的降解酶的产生。（NT-3的假定受体），它们不表达TrkA，高亲和力的NGF受体。应用地高辛标记的人p75（NTR）和NGF的正、反义核酸探针进行原位杂交，研究p75（NTR）和NGF mRNA的表达与人黑色素瘤脑转移的关系。我们检测到p75（NTR）mRNA在人类黑色素瘤脑转移瘤的侵袭前沿，而p75（NTR）的表达在邻近组织中没有发现。相反，人NGFmRNA水平在黑色素瘤病变周围组织中增加，支持NGF和NT在确定黑色素瘤脑转移微环境中很重要的观点。使用p75（NTR），TrkC，NGF和相关NT的特异性抗体，我们发现高，但异质性水平的p75（NTR）和TrkC表达的恶性黑色素瘤转移到脑。在原发性黑色素瘤或转移到脑以外部位的黑色素瘤中发现较低水平的表达。此外，我们发现在黑色素瘤病变周围的脑组织中，NGF和NT-3的合成水平升高，但脑源性神经营养因子（BDNF）或NT-4/5的合成水平没有升高。这些研究支持NT及其受体在黑色素瘤进展为脑转移表型中的作用。
Neurotrophins (NT), such as nerve growth factor (NGF), stimulate the growth and differentiation of several neuronal subpopulations in a distinct yet overlapping manner. Brain-metastatic human melanoma cells overexpress p75(NTR), the low-affinity neurotrophin receptor, and treatment of brain-metastatic cells with NGF stimulates extracellular matrix invasion and production of degradative enzymes in relation to the cellular expression of p75(NTR) Although human melanoma cells express high affinity neurotrophin receptors, such as TrkC (the putative receptor for NT-3), they do not express TrkA, the high-affinity NGF receptor. Using digoxigenin-labeled sense/antisense riboprobes against human p75(NTR) and NGF for in situ hybridization, we determined whether the expression of p75(NTR) and NGF mRNAs are related to brain metastasis of human melanoma. We detected p75(NTR) mRNA at the invasion front of human melanoma brain metastases, whereas p75(NTR) expression was not found in adjacent tissues. In contrast, human NGF mRNA levels were increased in tissues surrounding the melanoma lesions, supporting the notion that NGF and NT are important in determining melanoma brain-metastatic microenvironment. Using antibodies specific to p75(NTR), TrkC, NGF and related NT we found high but heterogeneous levels of p75(NTR) and TrkC expression in malignant melanomas metastatic to the brain. Lower levels of expression were found in primary melanomas or in metastatic melanomas to sites other than brain. Additionally, we found elevated levels of synthesis of NGF and NT-3 but not brain-derived neurotrophic factor (BDNF) or NT-4/5 in the brain tissues surrounding melanoma lesions. These studies support a role for NT and their receptors in the progression of melanomas to the brain-metastatic phenotype.