Abstract
Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR) heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs) from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR+) CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total) were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population.
Highlights
Solid tumors are in a constant state of evolution with progressive heterogeneity [1,2]
The fact that disseminated tumor cells can be detected in the blood of prostate cancer (PCa) patients after prostatectomy [6] suggests that Circulating tumor cells (CTCs) can be shed from either residual tumor in the prostate bed or from metastatic deposits
We developed a protocol for assessing the presence of live CTCs based on the active uptake of prototype IR-783 heptamethine carbocyanine dye [19,20]
Summary
Solid tumors are in a constant state of evolution with progressive heterogeneity [1,2]. The fact that disseminated tumor cells can be detected in the blood of PCa patients after prostatectomy [6] suggests that CTCs can be shed from either residual tumor in the prostate bed or from metastatic deposits. Molecular investigation of these cells may provide real-time information on the status of malignant progression. As the collection of CTCs typically requires low-volume standard phlebotomy, some have proposed that CTCs may be exploited as an ideal surrogate tissue or liquid biopsy to gauge disease status [7]. Such a source of tissue would provide a simple, minimallyinvasive tissue source that could be accessed serially to provide high temporal definition of the evolution of underlying disease
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