When cancer develops in the body, cancer cells that invade the bloodstream and circulate throughout the body; CTCs (Circulating Tumor Cells) are found from the early stages of cancer development. However, CTCs are difficult to capture because their concentration in the blood is extremely low, and their use in cancer treatment only began around 2000 with the development of CellSearch® (Medical Progress (Ishiyaku Shuppan) Vol. 228 No. 11 P1079), which was approved by the U.S. Food and Drug Administration.
CellSearch® has been approved for use in colorectal cancer, prostate cancer, and breast cancer, primarily to measure CTC concentrations in blood and predict prognosis, but has also been widely used in other cancers, such as lung cancer. As a result, it was found that CellSearch® does not necessarily detect CTCs with high sensitivity in various cancers, and in recent years, it has become important to collect CTCs and perform genetic analysis. As such, the technology to use CTCs in cancer treatment is still insufficient, and its development is continuing worldwide. The founder of Cytona recognized the importance of CTCs early on, and began research into capture devices in 2009, developing the Polymer CTC Chip.
Basic performance evaluation of Polymer CTC Chip
The basic performance of a CTC capture device is usually indicated by its "capture ratio", which is expressed as:
Capture efficiency: (Number of cancer cells captured by the device) / (Number of cancer cells flowing into the device) x 100%
The capture efficiency of the polymer CTC chip is being evaluated for cancer cell lines derived from various organs in collaboration with research institutes around the country. In the capture test, capture targets that match the properties of the cancer cells are selected, and antibodies against them are coated on the chip surface. In addition to the commonly used EpCAM, EGFR, HER2, podoplanin, etc. are also selected as capture targets. Depending on the cancer cell, it may be effective to use multiple capture targets, in which case the appropriate antibodies are mixed and coated on the chip.
Cancer cell lines captured on chip
Cancer cell capture performance of polymer CTC chip （Evaluated in PBS）
In collaboration with university hospitals, we are conducting clinical research on polymer CTC chips using blood samples for various types of cancer. The research themes are as follows, and we have demonstrated that CTCs can be used not only to obtain information on cancer cells, but also for a wide range of other purposes in cancer treatment and research (related published papers are in parentheses).
CTC detection rate and count (see below)
Monitoring of therapeutic effects and prognosis prediction using CTCs (Cancer Sci. 110, 726-733 (2019), Cancer and Chemotherapy, Vol. 42, 1240 (2015), etc.)
Cancer detection using tumor markers and CTCs (Oncol Lett. 19, 2286-2294 (2020))
Analysis of therapeutic target markers and stem cell markers for CTCs (Oncol Lett. 18, 6397-6404 (2019) and others)
CTC collection and genetic analysis (Cancer Sci. 113, 1028-1037 (2022) and others)
Below we present some of the research results, but for more detailed information or research not listed here, please refer to published papers or contact us.
Cancer types in which clinical research using polymer CTC chips was conducted (research institutes)
Lung cancer (University of Occupational and Environmental Health, Kyoto University)
Breast Cancer (Toyama University)
Malignant pleural mesothelioma (University of Occupational and Environmental Health)
Esophageal cancer (Toyama University)
Colorectal cancer (University of Tokyo, Juntendo University)
Pancreatic cancer (Kyoto University)
Urological Cancer (Nippon Medical School)
Gynecological Cancer (Juntendo University)
Head and Neck Cancer (Kanazawa University)
Malignant brain tumors (Niigata University)
Bone and soft tissue sarcoma (Toyama University)
Childhood Cancer (Gunma University)
CTC detection rate
Using blood samples, we measured the percentage of patients with various cancers in whom CTCs were detected (CTC detection rate). In addition, to compare performance with existing CTC analysis devices, we evaluated the CTC detection rate against CellSearch®, the only device approved by the US FDA.
Both studies have demonstrated that the Polymer CTC Chip has an excellent CTC detection rate and is fully suitable for clinical application.
CTCｓcaptured on the chip
Colorectal cancer (Juntendo University)
CTC detection rate 92.3％（12/13）
Oncol Lett. 19, 2286-2294 (2020)
Colorectal cancer (University of Tokyo)
CTC detection rate 81.8％（9/11）
Oncol Lett. 18, 6397-6404 (2019)
Prostate cancer (Nippon Medical School)
CTC detection rate 100％（14/14）
Prostate International 7, 131-138 (2019)
Lung Cancer (University of Occupational and Environmental Health, Japan)
CTC detection rate 58.1％（18/31）
Cancer Sci. 113, 1028-1037 (2022)
Malignant pleural mesothelioma (University of Occupational and Environmental Health, Japan)
CTC detection rate 73.7％（14/19）
Oncol Lett. 22, 522-530 (2021)
Polymer CTC Chip vs. CellSearch (US FDA approved device)
Polymer CTC Chip
CellSearch
Lung Cancer
Detection rate 58.1％（18/31）
Detection rate 25.8％（8/31）
Malignant pleural mesothelioma
Detection rate 68.8％（11/16）
Detection rate 6.3％（1/16）
Cancer Sci. 113, 1028-1037 (2022) ／ Cancer Sci. 110, 726-733 (2019)
CTC Recovery from Chips
To obtain detailed cancer information from CTCs captured on a chip, it is necessary to recover them. Such recovery is possible by conventional methods using micromanipulators and micropipettes (see below), and has been performed in previous clinical studies. Cytona has already established the following method in collaboration with universities.
To use air foam to peel off 100% of the CTCs on the chip and collect them by pouring them out of the chip while they are still alive
To collect specified CTCs after embedding all cells on the chip in the gel using a redissolvable gel material
Recovery of cells with micromanipulators or micropipettes
Genetic Analysis of Recovered CTCs
Genetic analysis of CTCs recovered from chips clinical studies has so far yielded the following results.
CTC malignancy is confirmed by genetic mutation (proves that CTCs are cancer cells).
CTC analysis of important genetic mutations in lung cancer (EGFR mutation, KRAS mutation) confirmed that the same mutations as in the histological examination were found.
Established a protocol for next-generation sequencing analysis of single-cell CTCs.
Below is an example of a genetic analysis test performed on cancer cells captured and collected on a chip using a cancer cell line prior to analyzing a patient's CTCs.
Genetic Analysis Testing of Recovered Cells
PC9 cells (a lung cancer cell line with a deletion mutation in EGFR exon19) were captured on a polymer CTC chip, and the deletion mutations were analyzed by PCR in micropipette-recovered cells. As a result, DNA showing a deletion mutation similar to that in bulk PC9 cells was found in the recovered cells.
PCR sample
Single cells recovered from chips ① to ④
Positive control: bulk PC9 cells
Negative control: bulk NCI-H441 cells (lung cancer-derived cell line, EGFR exon19 wild type) and water
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