The precursors for colorectal cancer include polypoid (conventional), flat and serrated adenomas. Polypoid growth in polypoid adenomas and serrated adenomas is associated with K-ras mutations. The regulation of polypoid or nonpolypoid growth is not well known, but could be related to trophic stimuli, such as thyroid hormones. Hence, we investigated the expression pattern of thyroid hormone receptor TRb1 in colorectal mucosa and in colorectal tumours and its relationship to tumour growth type. One hundred fourteen colorectal carcinoma specimens were evaluated for TRb1. Normal mucosa, adjacent adenomatous component (N 5 46) and lymph node metastases (N 5 28) were analysed when present, and the results were confirmed by Western blot analysis in selected cases. Nuclear TRb1 was almost always present in normal epithelium (96%), but less frequent in adenomas (83%) and in cancer (68%; p < 0.001 and p < 0.001, respectively). TRb1 was associated with polypoid growth, presence of K-ras mutations and also with a higher WHO histological grade and advanced Dukes' stage. Cytoplasmic expression of TRb1 was observed in nonneoplastic and neoplastic epithelium. In Western blot analysis, a 58 kDa band corresponding to TRb1 was expressed in normal mucosa and in colorectal cancer specimens with positive immunohistochemistry. Association of TRb1 expression with growth pattern and the presence of K-ras mutations suggest that abnormalities in thyroid hormone signalling involving TRb1 play a role in the development of some types of colorectal adenocarcinomas. ' 2005 Wiley-Liss, Inc.Key words: colorectal cancer classification; thyroid hormone receptors beta; K-ras oncogene Colorectal cancer evolves via a sequence of alterations. In addition to the well-known adenoma-carcinoma sequence, some colorectal cancers are thought to arise either de novo or from flat adenomas. These 2 pathways are biologically different, as K-ras mutations occur with high frequency in polypoid adenomas, but are rare in flat adenomas and carcinomas.1,2 It has been thought that the oncogenic action of mutated K-ras protein results in increased proliferation common in polypoid adenomas. 3Thyroid hormones regulate growth, development, differentiation and metabolic processes. 4 The actions of 3,3 0 ,5-triiodo-L-thyronine (T3) are mediated by thyroid hormone nuclear receptors (TR), which regulate the expression of T3-targeted genes. T3, thyroxin (T4), as well as its lower iodinated metabolites exert direct biological effects by mechanisms not involving nuclear T3-receptors.5 T3 and its receptors regulate processes such as cell proliferation, differentiation and apoptosis in normal tissues and in some malignancies. [6][7][8][9][10][11] Knockout mice models have shown that T3 receptor TRa, but not TRb, is involved in the maturation of the intestine. 12,13 TRs are members of the steroid hormone and retinoic acid superfamily of ligand-dependent transcription factors, and are derived from two genes, TRa and TRb, located on human chromosomes 17 and 3, respectively. Both gene...

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Disordered regulation of apoptosis occurs later in serrated pathway than in conventional adenoma-carcinoma pathway during malignant conversion. Serrated adenoma growth is not likely to be slower than adenoma growth, as judged by the proliferation and apoptosis rates in serrated adenomas and adenomas. In cancer, the decrease of proliferation and apoptosis in the invasive margin is likely to influence the behaviour of the tumour.

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