Shilkaitis A, Green A, Steele V, Lubet R, Kelloff G, Christov K
Department of Surgical Oncology, University of Illinois at Chicago, 840 South Wood Street M/C 820, Chicago, IL 60612, USA.
Carcinogenesis. 2000 Feb;21(2):227-33. doi: 10.1093/carcin/21.2.227.
Previous studies have shown that terminal end buds (TEBs) in the murine mammary gland have high proliferative activity and demonstrate apoptotic cell death (ACD). Since TEBs are considered the place of origin of most chemically induced mammary carcinomas, we hypothesized that the development of hyperplastic and premalignant (carcinoma in situ, CIS) lesions in TEBs is associated with either a further increase in cell proliferation and/or with a decrease in ACD. To test this hypothesis we used the N-methyl-N-nitorosourea (MNU) carcinogenesis model in rats, where the occurrence of mammary tumors is preceded by hyperplastic and premalignant lesions arising mostly in TEBs, as well as in ducts and alveoli. The percentage of proliferating cells, as evaluated by 5-bromodeoxyuridine labeling (BrdU-LI), was similar in TEBs to those in terminal endbud hyperplasia (TEBH), CIS, and carcinomas (CA), whereas the percentage of apoptotic cells (apoptotic index, AI) was relatively high in TEBs and decreased in TEBH, CIS, and CA. This indicates that neoplastic transformation of mammary epithelial cells in TEBs is not associated with an increase in cell proliferation, but with a decrease in ACD. In addition to TEBH, hyperplastic lesions developed in ductal branching areas (ductal hyperplasia, DH) and alveolar structures (alveolar hyperplasia, AH). However, BrdU-LI in both DH and AH was lower than in TEBH, whereas the AI values were similar, suggesting that TEBH has a higher potential for progression and malignant transformation than DH and AH. In mammary tumors apoptotic cells were rare in the peripheral, proliferative areas, but frequent close to the necrotic areas, suggesting that intratumoral factors may significantly affect ACD. Thus, it appears that dissociation between cell proliferation and apoptosis occurs in the hyperplastic stages of mammary carcinogenesis and that neoplastic transformation of mammary epithelial cells is associated with decreased ACD but not with increased cell proliferation.
先前的研究表明，小鼠乳腺中的终末芽（TEB）具有较高的增殖活性，并表现出凋亡性细胞死亡（ACD）。由于TEB被认为是大多数化学诱导的乳腺癌的起源部位，我们推测TEB中增生性和癌前（原位癌，CIS）病变的发展与细胞增殖的进一步增加和/或ACD的减少有关。为了验证这一假设，我们在大鼠中使用了N-甲基-N-亚硝基脲（MNU）致癌模型，在该模型中，乳腺肿瘤的发生之前会出现增生性和癌前病变，这些病变主要发生在TEB以及导管和腺泡中。通过5-溴脱氧尿苷标记（BrdU-LI）评估的增殖细胞百分比，在TEB中与终末芽增生（TEBH）、CIS和癌（CA）中的相似，而凋亡细胞百分比（凋亡指数，AI）在TEB中相对较高，在TEBH、CIS和CA中则降低。这表明TEB中乳腺上皮细胞的肿瘤转化与细胞增殖的增加无关，而是与ACD的减少有关。除了TEBH，在导管分支区域（导管增生，DH）和腺泡结构（腺泡增生，AH）也出现了增生性病变。然而，DH和AH中的BrdU-LI均低于TEBH，而AI值相似，这表明TEBH比DH和AH具有更高的进展和恶性转化潜力。在乳腺肿瘤中，凋亡细胞在周边增殖区域很少见，但在坏死区域附近很常见，这表明肿瘤内因素可能会显著影响ACD。因此，似乎在乳腺癌发生的增生阶段，细胞增殖与凋亡之间发生了解离，并且乳腺上皮细胞的肿瘤转化与ACD的降低有关，而与细胞增殖的增加无关。
