Biopsy and FNAC are invasive procedures, especially in the case of deeply located tumors, and may present severe complications such as infection, bleeding, or inflammation. More importantly, they also carry the risk of seeding tumor cells around the sampling area. Indeed, detached cells can be cleared by interstitial fluids to lymph nodes, or into the veins draining the tissue, thus entering the circulation.
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They might then extravasate at distant healthy tissues and contribute to metastasis formation. In particular, the outcome of pancreatic cancer is highly unpredictable, even in the case of resectable tumors, because predictive and prognosis colorectal cancer cell lines are missing Zhou et al.
Tumor elements are released very early during cancer development. For example, in a mouse model of pancreatic cancer, CTCs with metastatic potential are already shed during the formation of the primary pancreatic adenocarcinoma, before it becomes detectable by histologic methods Rhim et al. Liquid biopsies can also be used to detect disease progression or treatment resistance before the appearance of the first clinical signs Mari romani parazitii et al.
From the s, the interest on CTCs has gradually increased thanks to the progress in the detection methods based on molecular biology techniques. In the last 20 years, new technologies for CTC enrichment, detection, and characterization with higher sensitivity have been developed, allowing CTC numeration in different solid cancers Lianidou et al.
Most studies have focused on CTC detection and counting in peripheral blood samples obtained by puncture of the median cubital vein. Fewer reports have tested the hypothesis that the chances of capturing and detecting CTCs might be higher in vessels closer to the tumor, especially in the main veins that drain blood from the organ invaded by the cancer.
Basis for CTC analysis in the main veins close to the tumor site The primary tumor releases a heterogeneous population of circulating cells, such as cells with metastatic potential, apoptotic or necrotic cells that are cleared by the organism, and live cells that can remain in a latent or dormant state in a distant organ Massagué and Obenauf, ; Nguyen et al. CTCs are disseminated mostly during metastasis formation.
In fact, very few of the tumor cells released into the circulation will form metastases Kessenbrock et al. Consequently, cells detach from the tumor and spread out, using the surrounding fluids to move away, and enter the vessels by extravasation Tam and Weinberg, ; Thiery et al.
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The first capillary bed that a metastatic cell encounters depends on the blood circulation pattern near the primary tumor. In most organs, the venous circulation leads to the right ventricle of the heart and into the lungs, whereas the gut venous circulation drains into the liver. This explains the high incidence of metastases in lungs and liver Denève et al. For this reason, some authors have used blood samples from the vena cava upstream of the liver for CTC detection in patients with metastatic breast cancer colorectal cancer cell lines were obtained from an implanted vascular device Peeters et al.
As CTCs are rare events, a first enrichment step is required to allow their detection.
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CTCs can also be enriched and detected on the basis of their biological properties. These features are the basis of the CellSearch® system. After enrichment, the detection step is needed to confirm the presence of CTCs in the sample Alvarez Cubero et al.
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Despite improvements in the methods for CTC enrichment and detection, these cells remain rare in blood samples and difficult to identify. To maximize the chances of CTC recovery, it would seem logical to draw blood close to the site of the tumor.
In the case of CRC, HCC, and PDAC, the primary tumor is connected to the vascular draining territory of the mesenteric and portal venous system, whereas lung cancer is linked to the pulmonary vein.
These vessels are sufficiently large and resistant to allow direct vein puncture. Of note, the portal vein can be accessed by noninvasive ultrasonography puncture Chapman and Waxman, The pulmonary vein is reachable only during surgery, but it is a good candidate to capture more CTCs, with a high prognostic value Hashimoto et al.
Conversely, in breast cancer and prostate cancer, tumor elements are released mostly in the lymphatic network and the internal iliac vasculature, respectively.
As these draining systems cannot be punctured, CTC capture closer to the tumor has not been assessed in these cancer types. Pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma remains one of the deadliest cancers due to its late diagnosis and poorly efficient therapies Buscail, Moreover, treatment is often delayed due to difficulties in proving the presence of malignant lesions McGuigan et al.
CTC numeration in the peripheral blood of patients with PDAC has been assessed as a diagnostic option, but rather unsuccessfully due to the low detection rates Table S1. Most of these cohorts were quite small, and included only patients with metastatic or locally advanced tumors.
The most common site of PDAC spreading is the liver because the pancreas venous blood drains first into this organ Figure 1 Denève et al.
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The colorectal cancer cell lines filters pancreatic CTCs. If they do not stay in the liver, they will become highly diluted in the peripheral blood system i.
To increase the chances of CTC detection, blood was sampled directly from the portal vein prior to CTC sequestration in the liver Chapman and Waxman, This approach was first tested in 20 patients with resectable PDAC in whom portal blood could be easily and safely sampled during surgery Bissolati et al. Conversely, CTC detection in the portal vein sample was associated with higher rate of liver metastases Bissolati et al. The presence of CTCs in the portal blood was a predictive factor of liver metastasis.
Moreover, the absolute CTC numbers were higher in the portal blood samples The authors also evaluated the suitability of portal vein CTCs for gene expression studies. Similarly, in 29 patients with locally advanced and metastatic tumors Liu et al.
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Finally, in this study portal vein CTCs were cultured ex vivo to test the response to several common chemotherapies. Moreover, CTC viability was reduced by deltarasin Liu et al.
This suggests that ex vivo CTC culture might be a valuable tool for choosing the best therapy for each patient.
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