Abstract
BackgroundCD97 knockdown impairs the metastatic capacity of SGC-7901 gastric cancer cells. However, the role of CD97 in the distant lymphatic premetastatic niche formation of gastric cancer remains unknown.MethodsExosomes and the soluble fraction were isolated from SGC-L (an SGC-7901-cell-derived highly lymphatic metastatic cell line) and CD97-knockdown (SGC-L/CD97-kd) cells, and were co-cultured with gastric cancer cells. The metastatic capacity of the two cell lines was evaluated in vitro and in a footpad lymph node metastasis mouse model. Premetastatic-niche-formation-related proteins were examined immunohistochemically.ResultsCD97 expression was ninefold higher in SGC-L cells than in SGC-7901 cells. In vitro, exosomes or conditioned medium from the SGC-L cells enhanced cell proliferation (20 % increase) and invasion (30 % increase) as compared with that from SGC-L/CD97-kd cells (p < 0.01). Intrafootpad injections of SGC-L, but not SGC-L/CD97-kd exosomes or conditioned medium, strongly promoted SGC-L and SGC-L/CD97-kd cell accumulation in the draining lymph nodes (p < 0.01) and increased CD55, CD44v6, α5β1, CD31, epithelial cell adhesion molecule, and CD151 expression. Although the SGC-L/CD97-kd exosomes alone were insufficient for promotion of metastasis, they were partly aided by the SGC-L-cell-derived soluble fraction.ConclusionsThe CD97 small isoform promotes SGC-L cell lymphatic metastasis exosome dependently, and aided by the soluble fraction, the exosome-dependent CD97 plays a pivotal role in premetastatic niche formation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-015-0523-y) contains supplementary material, which is available to authorized users.
Highlights
Lymphatic metastasis is the commonest means of gastric carcinoma spread [1]
Elevated CD97 expression and CD44 and CD31 expression were found in the early metastatic regional lymph nodes of an orthotopically implanted gastric cancer mouse model, but their expression was strongly downregulated in a CD97/EGF1,2,5 knockdown group [7], which demonstrated that CD97 supports local tumor growth, and promotes lymph node metastasis
We used a mouse footpad lymph node metastasis model and the highly lymphatic metastatic SGC-L cell line to demonstrate that CD97 small isoform (CD97iso) promotes gastric cancer cell metastasis exosome dependently
Summary
Lymphatic metastasis is the commonest means of gastric carcinoma spread [1]. In metastasis formation, cancer-initiating cells detach from the local tumor and travel to the premetastatic niche in the target organ, organized by longdistance communication [2]. Elevated CD97 expression and CD44 and CD31 expression were found in the early metastatic regional lymph nodes of an orthotopically implanted gastric cancer mouse model, but their expression was strongly downregulated in a CD97/EGF1,2,5 knockdown group [7], which demonstrated that CD97 supports local tumor growth, and promotes lymph node metastasis. It was reported that tumor-derived exosomes contribute to metastatic niche formation and promote tumor growth in breast cancer [10]. Capitalizing on their long-distance gene-delivering characteristic, exosomes are considered mediators of the intercellular communication between the local tumor and the premetastatic niche in the host organs, which facilitates gastric carcinoma metastasis by promoting premetastatic niche formation. The role of CD97 in the distant lymphatic premetastatic niche formation of gastric cancer remains unknown
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