Jechorek Doerthe, Votapek Julia, Meyer Frank, Kandulski Arne, Roessner Albert, Franke Sabine
Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Department of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Pathol Res Pract. 2014 Dec;210(12):822-9. doi: 10.1016/j.prp.2014.08.014. Epub 2014 Sep 18.
The lysosomal cysteine carboxypeptidase cathepsin X (CTSX), localized predominantly in immune cells, has been associated with the development and progression of cancer. To determine its specific role in colorectal carcinoma (CRC), we analyzed CTSX expression in non-malignant mucosa and carcinoma of 177 patients as well as in 111 adenomas and related it with clinicopathological parameters. Further, the role of CTSX in the adhesion and invasion of the colon carcinoma cell lines HT-29 and HCT116 was investigated in an in vitro culture cell system with fibroblasts and monocytes, reflecting the situation at the tumor invasion front. Epithelial CTSX expression significantly increased from normal mucosa to adenoma and carcinoma, with highest expression levels in high grade intraepithelial neoplasia and in early tumor stages. Loss of CTSX occurred with tumor progression, and correlated with advanced local invasion, lymph node and distal metastasis, lymphatic vessel and vein invasion, tumor cell budding and poorer overall survival of patients with CRC. The subcellular distribution of CTSX changed from vesicular paranuclear expression in the tumor center to submembranous expression in cells of the invasion front. Peritumoral macrophages showed highest expression of CTSX. In vitro assays identified CTSX as relevant factor for cell-cell adhesion and tumor cell anchorage to fibroblasts and basal membrane components, whereas inhibition of CTSX caused increased invasiveness of colon carcinoma cells in mono- and co-culture. In conclusion, CTSX is involved in early tumorigenesis and in the stabilization of tumor cell formation in CRC. The results suggest that loss of CTSX may be needed for tumor cell detachment, local invasion and tumor progression. In addition, CTSX in tumor-associated macrophages indicates a role for CTSX in the anti-tumor immune response.
溶酶体半胱氨酸羧肽酶组织蛋白酶X（CTSX）主要定位于免疫细胞，与癌症的发生和发展有关。为了确定其在结直肠癌（CRC）中的具体作用，我们分析了177例患者的非恶性黏膜和癌组织以及111例腺瘤中CTSX的表达情况，并将其与临床病理参数相关联。此外，在含有成纤维细胞和单核细胞的体外培养细胞系统中研究了CTSX在结肠癌细胞系HT - 29和HCT116的黏附及侵袭中的作用，该系统反映了肿瘤侵袭前沿的情况。上皮CTSX表达从正常黏膜到腺瘤和癌显著增加，在高级别上皮内瘤变和肿瘤早期阶段表达水平最高。CTSX的缺失随肿瘤进展而出现，并与局部侵袭进展、淋巴结和远处转移、淋巴管和静脉侵袭、肿瘤细胞芽生以及CRC患者较差的总生存率相关。CTSX的亚细胞分布从肿瘤中心的泡状核旁表达转变为侵袭前沿细胞的膜下表达。肿瘤周围巨噬细胞显示CTSX表达最高。体外试验确定CTSX是细胞间黏附以及肿瘤细胞与成纤维细胞和基底膜成分锚定的相关因子，而抑制CTSX会导致结肠癌细胞在单培养和共培养中的侵袭性增加。总之，CTSX参与CRC的早期肿瘤发生和肿瘤细胞形成的稳定。结果表明，肿瘤细胞脱离、局部侵袭和肿瘤进展可能需要CTSX的缺失。此外，肿瘤相关巨噬细胞中的CTSX表明CTSX在抗肿瘤免疫反应中发挥作用。
