Dolcetti R, Boiocchi M
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano (PN), Italy.
Clin Exp Rheumatol. 1996 Jan-Feb;14 Suppl 14:S3-13.
The concept that lymphomagenesis is a multistep process is now widely accepted. Various factors are involved in the development and malignant progression of B-cell lymphoproliferative disorders. The most frequently recognized alterations in these disorders are chromosomal translocations which lead to the activation of proto-oncogenes (c-myc) or genes encoding for proteins involved in the control of the cell cycle (cyclin D1), differentiation (bcl-6) and apoptosis (bcl-2). In addition, genetic changes that inactivate tumor suppressor genes (p53, Rb, p16) have recently been identified. Infectious agents may also play a role in lymphomagenesis either by directly driving B-cell proliferation (EBV) or by inducing a chronic antigenic stimulation (EBV, HCV, HBV, helicobacter pylori). Finally, several data indicate that local cytokine networks and, in particular, autocrine (IL-6, IL-10) and/or paracrine (IL-2, IL-4, IL-6) loops probably play a contributory role in the development and evolution of B-cell lymphoproliferation. In the last few years, the advent of molecular biology techniques has allowed important advances in the definition of the events involved i the earlier phases of lymphoma development. This has been made possible, in particular, by the study of a series of oligoclonal or monoclonal lymphoproliferative disorders characterized by an indolent or "smoldering" clinical course, such as follicular lymphoma and the lymphoproliferation associated with autoimmune diseases, which are at high risk of evolution to a highly malignant lymphoma. In nearly all of these conditions, the clonal B-cells responsible for the early stages of the disease are probably not fully transformed and retain various degrees of responsiveness to a wide variety of microenvironmental stimuli (antigen or autoantigen stimulation, interactions with "reactive" T lymphocytes, local cytokine networks). These latter in turn may induce the regression of pathological lesions, maintain the disease in an active state or contribute to the evolution towards an overtly malignant lymphoma. These findings open new avenues for the design of unconventional strategies of intervention aimed at preventing the malignant evolution of pre-lymphomatous lesions and controlling the clinical course of certain low-grade B-cell lymphomas.
淋巴瘤发生是一个多步骤过程的概念现在已被广泛接受。多种因素参与了B细胞淋巴增殖性疾病的发生和恶性进展。这些疾病中最常被认识到的改变是染色体易位，其导致原癌基因（c-myc）或编码参与细胞周期控制（细胞周期蛋白D1）、分化（bcl-6）和凋亡（bcl-2）的蛋白质的基因被激活。此外，最近还发现了使肿瘤抑制基因（p53、Rb、p16）失活的基因变化。感染因子也可能在淋巴瘤发生中起作用，要么通过直接驱动B细胞增殖（EBV），要么通过诱导慢性抗原刺激（EBV、HCV、HBV、幽门螺杆菌）。最后，一些数据表明局部细胞因子网络，特别是自分泌（IL-6、IL-10）和/或旁分泌（IL-2、IL-4、IL-6）环路可能在B细胞淋巴增殖的发生和演变中起促进作用。在过去几年中，分子生物学技术的出现使得在淋巴瘤发生早期阶段所涉及事件的定义方面取得了重要进展。这尤其通过对一系列以惰性或“潜伏性”临床病程为特征的寡克隆或单克隆淋巴增殖性疾病的研究得以实现，例如滤泡性淋巴瘤以及与自身免疫性疾病相关的淋巴增殖，这些疾病有发展为高度恶性淋巴瘤的高风险。在几乎所有这些情况下，负责疾病早期阶段的克隆性B细胞可能并未完全转化，并且对多种微环境刺激（抗原或自身抗原刺激、与“反应性”T淋巴细胞的相互作用、局部细胞因子网络）保持不同程度的反应性。后者反过来可能诱导病理病变的消退、使疾病维持在活跃状态或促进向明显恶性淋巴瘤的演变。这些发现为设计非传统干预策略开辟了新途径，旨在预防淋巴瘤前期病变的恶性演变并控制某些低级别B细胞淋巴瘤的临床病程。
