Crypt restricted heterogeneity of goblet cell mucus glycoprotein in histologically normal human colonic mucosa: a potential marker of somatic mutation.
Crypt restricted heterogeneity of goblet cell mucus glycoprotein in histologically normal human colonic mucosa: a potential marker of somatic mutation.
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DOI：
10.1038/bjc.1990.83
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发表时间：
1990-03
影响因子：
8.8
通讯作者：
Williams ED
中科院分区：
文献类型：
--
作者：
Fuller CE;Davies RP;Williams GT;Williams ED
目前来自实验动物的证据表明，结肠隐窝是来源于单细胞并由单细胞维持的克隆单位（Griffiths等人，1988年）。用结肠特异性致癌物二甲基肼（DMH）处理正常雌性TO品系小鼠，结果在单个随机分布的结肠隐窝中，X-连锁酶葡萄糖-6-磷酸脱氢酶（G6 PD）的活性丧失，这在组织化学上是可证实的。这种表型变化在受影响的隐窝内是一致的，并且其频率与DMH处理的剂量相关，强烈表明这是单个原代隐窝干细胞的活性X染色体上的G6 PD基因座处的致癌物诱导突变的结果（Griffiths等人，使用轻度高碘酸-希夫（mPAS）技术在正常人大肠粘膜中已经证明了类似的隐窝限制性表型变化（Sugihara和Jass，1986）。该组织化学方法区分了0-乙酰化唾液酸粘蛋白（其为mPAS阴性）和非0-乙酰化唾液酸粘蛋白（其染成洋红色）（Veh et al.，1982年）。Sugihara和Jass（1986）发现在大多数人结肠中杯状细胞粘液是O-乙酰化的和mPAS阴性的，但在一小部分个体中杯状细胞粘液是非O-乙酰化的和弥漫性mPAS阳性的。然而，在一些mPAS阴性结肠粘液糖蛋白的病例中，他们观察到分散的单个mPAS阳性隐窝。他们不确定其意义，但将其解释为“功能性化生”。Hughes et al.（1986），他描述了针对结肠杯状细胞的单克隆抗体（3 NM）的免疫反应性的局灶性丧失，再次局限于人大肠中分散的隐窝。由于这两份报告中描述的隐窝限制性表型改变与诱变剂诱导的实验小鼠结肠隐窝G6 PD活性丧失相似，我们认为它们可能是由隐窝干细胞突变引起的。如果这是正确的，受影响的隐窝的频率将随着暴露于诱变剂而增加，并且与年龄有关。这种变化也可能更频繁地发生在结直肠癌受试者中。我们
Current evidence from experimental animals suggests that the colonic crypt is a clonal unit derived from, and maintained by, a single cell (Griffiths et al., 1988). Treatmentof normal female TO strain mice with the colon-specific carcinogen dimethylhydrazine (DMH) results in a histochemically demonstrable loss of activity of the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) in single, randomly dis-tributed colonic crypts. This phenotypic change is uniform within the affected crypts, and its frequency is related to the dose of DMH treatment, strongly suggesting that itis the result of a carcinogen induced mutation at the G6PD locus on the active X-chromosome of a single primary crypt stem cell (Griffiths et al., 1988).A similar crypt-restricted phenotypic change has been demonstrated in normal human large bowel mucosa using the mild periodic acid-Schiff (mPAS) technique (Sugihara & Jass, 1986). This histochemical method distinguishes between 0-acetylated sialomucins, which are mPAS-negative, and non-0-acetylated sialomucins which stain a magenta colour (Veh et al., 1982). Sugihara and Jass (1986) foundthat in most human colons the goblet cell mucus is O-acetylated and mPAS-negative but thatin a small proportion of individuals it is non-O-acetylated and diffusely mPAS-positive. However, in some cases with mPAS-negative colonic mucus glycoproteins they observed scattered individual mPAS-positive crypts. They were uncertain of the significance of this but interpreted it as a'functional metaplasia'. A similar phenomenon has been identified by Hughes et al.(1986), who described a focal loss of immunoreactivity to a monoclonal antibody (3NM) directed against colonic goblet cells, again confined to scattered crypts inthe human large intestine. Because the crypt-restricted phenotypic alterations described in these two reports are similar to the mutagen-induced loss of G6PD activity in the colonic crypts of experi-mental mice, we considered that they may result from crypt stem cell mutation. If this were correct, the frequency of affected crypts would increase with exposure to environmen-tal mutagens, and be age-related. The change might also occur more frequently in subjects with colorectal cancer. We