Abstract
Circulating tumor cells have emerged as biomarkers for estimating the tumor burden and metastatic potential of cancer patients. However, to date, most of studies and applications of circulating tumor cells have been conducted and applied to epithelial cancers such as breast, colorectal, and prostate tumor. The only FDA-cleared method, CellSearch, makes use of antibody against epithelial surface protein expressed on CTCs, thus obstructing wide application for various cancers with non-epithelial and semi-epithelial characteristics including renal cell carcinoma. Due to rarity and ambiguity of CTCs, designed experiment including non-biased CTC isolation and subsequent cytopathological study for finding applicable immunomarkers are urgently needed for clinical use of CTCs for less-studied cancers. Here, in order to construct the fundamental step for CTC diagnosis without limitation of its epithelial characteristics, we present the simple and novel method which incorporate both label-free CTC isolation and pathological study using hydrogel-based cell block formation. Six cell lines from lung, ovarian, kidney cancers were used to make cell block and analyzed by conventional immunocytochemical staining method to find the candidate markers for CTC. Especially for renal cancer, the physically isolated CTCs were further immunocytochemically examined with the screened candidate markers by cell block construction, and verified their clinical utility using blood samples from patients with renal cell carcinoma. This comprehensive study demonstrates that the present approach can be used to find the potential markers for any type of cancers regardless of their epithelial characteristics and isolate the specific type of CTCs in label-free manners.
Highlights
Circulating tumor cells (CTCs) is defined as tumor cells shed from the primary tumor site, circulating along the blood vessels, forming secondary tumor, which is called metastasis
The so-called ‘gold standard’ of CTC-based diagnostic tool, CellSearch, and its following CTC isolation techniques[2,3] mostly rely on the antibody against epithelial cell adhesion molecule (EpCAM), which is normally expressed on epithelial cancer cells only
Despite the recent advances in diagnostic tools and biochemical researches, a few molecular markers for Renal cell carcinoma (RCC) have been identified to predict the response from specific therapies
Summary
Circulating tumor cells (CTCs) is defined as tumor cells shed from the primary tumor site, circulating along the blood vessels, forming secondary tumor, which is called metastasis. In some types of tumor cells, EpCAM expression is down-regulated and even in epithelial cancers, the expression level of EpCAM can be turned into weak- or negligible level after epithelial-mesenchymal transition (EMT), which is natural and inevitable pathway of tumor progression[4] To overcome this limitation, label-free circulating tumor cell isolation methodologies[5,6,7,8] have been studied and shown comparable or even higher detection sensitivity on certain cancers with the possibility on systematic study of CTCs9,10. The fluorescence activated cell sorters (FACS), one of the SCA methods, had been applied to find the expression patterns in proteins on cells Recently this technique successfully captured single CTC, its inherent systematic losses of cells remained problematic. Similar to RCC, other type of cancers, including lung and ovarian still have difficulty in capturing heterogeneous CTCs and finding clinical importance of CTCs captured by EpCAM-based methods
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