Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells

Abstract

Circulating tumor cell (CTC) detection and numeration are becoming part of the common clinical practice, especially for breast, colon, and prostate cancer. However, their paucity in peripheral blood samples is an obstacle for their identification. Several groups have tried to improve CTC recovery rate by developing highly sensitive cellular and molecular detection methods. However, CTCs are still difficult to detect in peripheral blood. Therefore, their recovery rate could be increased by obtaining blood samples from vessels close to the drainage territories of the invaded organ, when the anatomical situation is favorable. This approach has been tested mostly during tumor resection surgery, when the vessels nearest to the tumor are easily accessible. Moreover, radiological (including echo-guided based and endovascular techniques) and/or endoscopic routes could be utilized to obtain CTC samples close to the tumor in a less invasive way than conventional biopsies. The purpose of this article is to summarize the available knowledge on CTC recovery from blood samples collected close to the tumor (i.e., in vessels located in the drainage area of the primary tumor or metastases). The relevance of such an approach for diagnostic and prognostic evaluations will be discussed, particularly for pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and non-small-cell lung cancer.

Keywords: cancer diagnostics; cancer prognosis; circulating tumor cells; liquid biopsy; vascular organ drainage.

Figure 1

CTC detection in the portal vein for patients with PDAC (★) or CRC (). Pancreatic cancer and colorectal cancer metastases in the liver () develop through multiple steps. Local invasion by cancer cells is followed by their intravasation into the tumor vasculature. Cancer cells then enter the porto‐mesenteric venous system as single cells or clusters that might be coated by platelets. CTCs are released in the superior and inferior mesenteric (green circle) veins for CRC in the right colon and left colon/rectum, respectively, and in the portal vein (red circle) for PDAC. Portal blood flows through the liver and then to other distant organs, after crossing the liver capillaries in portal areas. CTCs follow the same route and might extravasate in the liver parenchyma to start colonization. Portal blood sampling before passage in the liver can allow improving CTC recovery rate. The blue arrows show the direction of the blood flow in the veins.

Figure 2

Detection of HCC‐derived CTCs in the hepatic and portal veins. The hepatic circulation is connected to the systemic circulation via three major vessels: the hepatic veins (green circle), which serve as the efferent pathway, and the hepatic artery and portal vein (red circle), which function as afferent vessels. HCC‐derived CTCs are released in the hepatic lobule (blue circle) in the portal branch () and in the central vein (★) that constitute the hepatic vein system draining into the inferior vena cava. They represent the main intrahepatic and pulmonary metastatic routes (). Blood sampling from the hepatic veins (green circle) could improve CTC detection.

Figure 3

NSCLC‐derived CTC detection in the pulmonary vein. NSCLC metastatic sites are primarily bone marrow, brain, and adrenal gland. First, CTCs extravasate in the circulation via the pulmonary veins (black circle). Then, CTCs go into the systemic circulation toward the cerebral capillaries (via the branches of the aortic arch (★)) or the bone marrow sinusoids and other distant sites. The fenestrated structure of bone marrow sinusoid capillaries is permissive to cancer cell infiltration. Brain capillaries are more difficult to penetrate, due to the unique nature of the blood–brain barrier. Based on the features of the pulmonary circulation, CTCs could be retained in the pulmonary vein (black circle), offering an opportunity to increase their detection in blood samples collected from this vein during tumor resection, as already shown by Bernaudin et al 2005.