Miraki-Moud F, Jenkins P J, Fairclough P D, Jordan S, Bustin S A, Jones A M, Lowe D G, Monson J P, Grossman A B, Besser G M, Camacho-Hübner C
Department of Endocrinology, St. Bartholomew's Hospital, London, UK.
Clin Endocrinol (Oxf). 2001 Apr;54(4):499-508. doi: 10.1046/j.1365-2265.2001.01221.x.
Patients with acromegaly are at increased risk of developing colorectal carcinoma and premalignant tubulovillous adenoma. The pathogenesis of these neoplasms could involve a stimulatory effect of serum growth factors on colonic epithelial cell proliferation. The aim of this study was to evaluate changes in (1) serum IGF-I, IGF-II, IGFBP-3 and IGFBP-2 and (2) changes in local expression of IGFBPs and p53 in colonic epithelium in patients with colonic neoplasia with and without acromegaly.
A cross-sectional retrospective study was performed. Fasting serum samples were obtained at the time of colonoscopy for patients with acromegaly and at the time of surgery for patients with colonic neoplasia without acromegaly.
Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured using specific immunoassays. Tissue expression of IGFBP-2, IGFBP-3 and p53 status were determined by immunohistochemistry.
Group 1: 26 age- and sex-matched control subjects (range 40-69 years); group 2: 18 patients with acromegaly without colonic neoplasia (range 39-68 years); group 3: 18 patients with acromegaly and colonic neoplasia (range 41-74 years, 11 = adenoma, seven = carcinoma); group 4: 19 patients with colonic neoplasia without endocrine disease (range 43-91 years, four = adenoma, 15 = carcinoma). Immunohistochemical staining of colonic biopsies was performed for IGFBP-2, IGFBP-3 and p53 in groups 3 and 4.
Mean serum IGF-I and IGFBP-3 levels were significantly elevated in group 2 (371 +/- 131 microg/l and 6.5 +/- 1.8 mg/l, respectively) and group 3 (379 +/- 174 microg/l and 5.8 +/- 1.6 mg/l, respectively), and significantly reduced in group 4 (103 +/- 36 microg/l and 2.4 +/- 1 mg/l) compared to controls (165 +/- 40 microg/l and 4.7 +/- 1 mg/l; P < 0.0001, P < 0.001, respectively). However, median serum IGFBP-2 levels were significantly elevated in group 3 (P < 0.01) and group 4 (P < 0.0001). Immunostaining for IGFBP-2 showed strong areas of immunoreactivity in the cytoplasm of malignant colonic epithelium compared to benign epithelium. IGFBP-3 immunostaining showed strong areas of immunoreactivity in the cytoplasm and in the nucleus of malignant and benign colonic epithelium compared to the normal epithelium. Nuclear staining for p53 was observed in three patients from group 3 (two carcinoma, one adenoma) and four patients from group 4 (all carcinoma).
Our results describe changes in IGFBP-2 expression in colonic neoplasia in patients with and without acromegaly, which suggest that this binding protein may regulate local bioavailability of IGF, which in turn could modulate colonic cell proliferation and/or differentiation.
肢端肥大症患者患结直肠癌和癌前管状绒毛状腺瘤的风险增加。这些肿瘤的发病机制可能涉及血清生长因子对结肠上皮细胞增殖的刺激作用。本研究的目的是评估（1）患有和未患有肢端肥大症的结肠肿瘤患者血清IGF-I、IGF-II、IGFBP-3和IGFBP-2的变化，以及（2）结肠上皮中IGFBPs和p53的局部表达变化。
进行了一项横断面回顾性研究。肢端肥大症患者在结肠镜检查时采集空腹血清样本，未患肢端肥大症的结肠肿瘤患者在手术时采集。
使用特异性免疫测定法测量血清IGF-I、IGF-II、IGFBP-2和IGFBP-3。通过免疫组织化学确定IGFBP-2、IGFBP-3的组织表达和p53状态。
第1组：26名年龄和性别匹配的对照受试者（年龄范围40 - 69岁）；第2组：18名无结肠肿瘤的肢端肥大症患者（年龄范围39 - 68岁）；第3组：18名患有肢端肥大症和结肠肿瘤的患者（年龄范围41 - 74岁，11例为腺瘤，7例为癌）；第4组：19名无内分泌疾病的结肠肿瘤患者（年龄范围43 - 91岁，4例为腺瘤，15例为癌）。对第3组和第4组的结肠活检组织进行IGFBP-2、IGFBP-3和p53的免疫组织化学染色。
与对照组（分别为165±40μg/l和4.7±1mg/l）相比，第2组（分别为371±131μg/l和6.5±1.8mg/l）和第3组（分别为379±174μg/l和5.8±1.6mg/l）的平均血清IGF-I和IGFBP-3水平显著升高，第4组（分别为103±36μg/l和2.4±1mg/l）显著降低（P < 0.0001，P < 0.001）。然而，第3组（P < 0.01）和第4组（P < 0.0001）的血清IGFBP-2中位数水平显著升高。与良性上皮相比，IGFBP-2免疫染色显示恶性结肠上皮细胞质中有强免疫反应区域。与正常上皮相比，IGFBP-3免疫染色显示恶性和良性结肠上皮细胞质和细胞核中有强免疫反应区域。在第3组的3名患者（2例癌，1例腺瘤）和第4组的4名患者（均为癌）中观察到p53核染色。
我们的结果描述了患有和未患有肢端肥大症的结肠肿瘤患者中IGFBP-（2）表达的变化，这表明这种结合蛋白可能调节IGF的局部生物利用度，进而可能调节结肠细胞的增殖和/或分化。
