Taken together, these results suggest that targeting the CD44v8-10 isoform will provide new therapeutic strategies to increase the disease-free survival rates of patients with AGC by eradicating metastasis

Taken together, these results suggest that targeting the CD44v8-10 isoform will provide new therapeutic strategies to increase the disease-free survival rates of patients with AGC by eradicating metastasis. Methods Goat polyclonal to IgG (H+L)(HRPO) Cell lines and patient stomach tissues Cell lines were obtained from ATCC (USA) (MKN-28, AGS, KATOIII, HCT-116, MDA-231, SK-BR-3, JIMT-1, U87MG, A549, CEM-119, HeLa, Jurkat and HDF) and from Korean Cell Line Bank (Seoul National University, Korea) (SNU-216, SNU-638, SNU-719, and SNU-C5) were cultured with designated media supplemented with 10% fetal bovine serum and 1x penicillin-streptomycin at 37?C 5% CO2 incubator. in stomach cancer cell lines as well as in 74 patients with AGC by using exon-specific qRT-PCR. Among the CD44v isoforms, CD44v8-10 was determined as the most promising biomarker for the development of theranostic agents of gastric cancer. Next, we synthesised the conjugate of anti-CD44v9 antibody with near-infrared fluorophore or photosensitiser, and then demonstrated its feasibility for target cell-specific imaging and photoimmunotherapy in gastric cancer. As a result, these conjugates have clearly demarcated the surface of CD44v8-10 expressing cancer cells and showed efficient phototoxic effects. Therefore, this study revealed that CD44v8-10 is the efficient theranostic biomarker to target disseminated cancer cells in AGC. Introduction Stomach cancer is the third leading cause of cancer death in both sexes worldwide (723,000 deaths, 8.8% of the total). In particular, the highest estimated mortality rates are in Eastern Asia (24 per 100,000 in men, 9.8 per 100,000 in women)1. Thus, it is necessary to develop a therapeutic strategy to overcome the high mortality rates caused by stomach cancer. Stomach cancer is composed of heterogeneous cell populations that manifest malignancy by aberrantly regulating cell proliferation, differentiation, angiogenesis, migration, and metastasis2, and its carcinogenic process is complex3, 4. To obtain a comprehensive understanding of the pathophysiological status of cancer at a molecular level, an enormous amount of genome data is being profiled and analysed worldwide, but the only approved biomarker of tumour response to targeted agents in advanced gastric cancer (AGC) is human epidermal growth receptor Monastrol (HER)-2. Although trastuzumab is an approved targeted therapeutic drug for the subgroup of (HER)-2-positive AGC, based on the results of a ToGA trial (phase III trastuzumab for gastric cancer), the majority of patients did not respond in the first-line setting. Therefore, identification of new biomarkers for detection and therapy of gastric cancer is an ongoing clinical challenge. The single-pass transmembrane glycoprotein CD44, which binds to hyaluronic acid, has also been recognized as one of the markers to fit the purpose. It is implicated in tumour cell invasion and metastasis5, as well as many physiological phenomena related to tumour formation including cell migration, invasion, and metastasis6. The CD44 gene has ten constant exons and ten variable exons (v1-v10) placed between exon 5 and 16, and multiple isoforms of CD44 molecules are generated via alternative mRNA splicing of the ten variable exons. While the standard isoform of CD44 (CD44s) is known to predominate in hematopoietic cells and normal epithelial cell subsets, many variant isoforms (CD44v) with the extended extracellular stalk region are more prevalent in epithelial carcinomas7. It was reported that the CD44v3,8-10 isoform was involved in the metastasis of breast cancer8 and colorectal adenomas9, and CD44v3 and CD44v6 for colorectal cancer10. Furthermore, CD44v6 and CD44v9 interact with CD95, the death receptor, interfering with death receptor signalling and inhibiting apoptosis11. Although the roles of CD44v in cancer stem cells (CSCs) remain elusive, it was reported that CD44(+) gastric cancer cells have the stem cell properties of self-regeneration and the ability to form differentiated programs when compared with CD44(?) cells12. Thus, CD44 variants might also be considered as susceptible targets for cancer stem cells13; however, this has not yet been confirmed2. Relapse of gastric cancer has been debated in terms of stem cell-like properties of cells in the lesions, and CD44v914 and CD44v8-10 isoforms12, 15 were suggested as predictive markers as well as molecules for targeting CSCs. In addition, CD44v8-10, which interacts with and thereby stabilizes xCT at the plasma membrane, was reported as the key component contributing to reactive oxygen species (ROS) defence through upregulation of the synthesis of reduced glutathione (GSH)5, 16. In addition, based on the idea that the binding between CD44 Monastrol and sodium hyaluronate is mediated by Monastrol many different intra/extracellular signalling pathways and is related to cancer proliferation and tumorigenesis17,.