Shed into the peripheral circulation from a primary tumor, circulating tumor cells (CTCs) are limited by their extremely sparse concentrations in blood. In contrast, molecular markers secreted by tumor cells into the vasculature are present in much higher concentrations and could provide important insight on cancer cell biology and predictive biomarkers for early detection, progression and metastasis. These markers, including soluble proteins, cell-free DNA (cfDNA), and circulating microvesicles and exosomes have been shown to contain valuable information on the molecular state of often difficult to access tumor sites. Unfortunately, the source of the soluble proteins found in blood cannot be determined, resulting in the high false-positive rates, while significantly more specific cfDNA often reflect the dying or apoptotic cells. Exosomes, small membrane vesicles of endocytic origin, show the greatest potential as an easily accessible biomarker for early cancer detection and monitoring due to their unique properties, including their stability in biological fluids and their potential to be efficiently isolated. Cancer cells release more exosomes than normal cells and exosomes secreted from tumor cells can promote tumor progression, survival, invasion and angiogenesis. In this application we propose to develop an optical spectroscopic technique, which combines light scattering spectroscopy (LSS) and surface enhanced Raman spectroscopy (SERS) for highly rigorous isolation and assessment of blood-circulating cancer exosomes for early cancer detection in a rapid and inexpensive lab-on-a-chip system. As it is shown in this application, not only LSS can separate exosomes from microvesicles, the capability not available at the moment, but it also can differentiate various types of exosomes originated in different organs of the digestive tract, while SERS is capable of differentiating exosomes secreted by cancerous and normal cells of the same organ.

Public Health Relevance

The molecular markers such as exosomes, small membrane vesicles that contain microRNAs, mRNAs, DNA fragments, and proteins, are shed from tumor cells into blood. As cancer cells release more exosomes than normal cells, the analysis of exosomes isolated from blood have great potential for early cancer detection and for clinical monitoring of the state of difficult to access tumor sites.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA218382-02
Application #
9631430
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Young, Matthew R
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Turzhitsky, Vladimir; Zhang, Lei; Horowitz, Gary L et al. (2018) Picoanalysis of Drugs in Biofluids with Quantitative Label-Free Surface-Enhanced Raman Spectroscopy. Small 14:e1802392