Giannoni Paolo, de Totero Daniela
Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy.
Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy.
Cancer Drug Resist. 2021 Oct 21;4(4):923-933. doi: 10.20517/cdr.2021.73. eCollection 2021.
Multiple myeloma (MM) accounts for about 10% of hematologic malignancies, and it is the second most frequent hematologic neoplasm after lymphomas. The exact etiology of MM is still unknown and, despite the introduction of more effective and safe drugs in recent years, MM remains an incurable disease. Intrinsic and acquired resistance of malignant B cells to pharmacological treatments still represents an obstacle for survival improvement. Activation of the hepatocyte growth factor/c-MET axis has been reported as involved in MM pathogenesis: hepatocyte growth factor (HGF) levels are in fact higher in sera from MM patients than in healthy controls, the HGF/c-MET pathway may be activated in an autocrine or paracrine manner, and it is interesting to note that a higher c-MET phosphorylation is associated with disease progression. Several studies have further demonstrated the over-activation of c-MET either in resistant cell lines or in primary malignant plasma cells purified from bone marrow of patients resistant to chemotherapy. For this reason, c-MET has been proposed as a potential marker of multidrug resistance in the disease. Here, we first summarize the potential role of HGF/c-MET interaction in disease evolution and then describe novel approaches targeting this axis which could be conceptually utilized, alone or in combination with standard therapies, to treat MM and possibly overcome drug resistance.
多发性骨髓瘤（MM）约占血液系统恶性肿瘤的10%，是仅次于淋巴瘤的第二常见血液肿瘤。MM的确切病因仍不清楚，尽管近年来引入了更有效、更安全的药物，但MM仍然是一种无法治愈的疾病。恶性B细胞对药物治疗的内在和获得性耐药仍然是改善生存的障碍。据报道，肝细胞生长因子/c-MET轴的激活与MM发病机制有关：事实上，MM患者血清中的肝细胞生长因子（HGF）水平高于健康对照，HGF/c-MET途径可能以自分泌或旁分泌方式被激活，值得注意的是，较高的c-MET磷酸化与疾病进展相关。多项研究进一步证明，在耐药细胞系或从化疗耐药患者骨髓中纯化的原发性恶性浆细胞中，c-MET存在过度激活。因此，c-MET被认为是该疾病多药耐药的潜在标志物。在此，我们首先总结HGF/c-MET相互作用在疾病发展中的潜在作用，然后描述针对该轴的新方法，这些方法理论上可单独或与标准疗法联合用于治疗MM，并可能克服耐药性。
