Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment

Abstract

The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as “seeds” in peripheral blood, then reach the target organ as dormant cells which could be subsequently “awakened” and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.

Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review

“…CTCs released from primary HCC tumors initially disseminate in the portal branch of the hepatic lobule, then circulate to the central vein, connecting to the hepatic vein system before spreading systemically throughout the body. A study into CTCs characteristics, which have been described as a conduit for metastatic events, provided detailed biological information on intrahepatic and extrahepatic recurrence in HCC [ 8 , 9 ].…”

Recent advances in recurrent hepatocellular carcinoma therapy

“…In HCC patients after surgery, higher interleukin (IL-11) levels enhanced tumor expansion, and in genetic mouse model, suppression of IL-11-STAT3 signaling greatly reduced cell proliferation and post-surgical recurrences of HCC tumors[ 27 ]. Local recurrence is caused by the invasion of local tumor blood flow and peritumoral diffusion, whereas systemic dissemination is caused by the “rehoming” of circulating tumor cells that have spread from the initial nodules[ 28 ]. HCC recurrence can occur as a result of tumor cells that are circulating or at rest, evading the host’s immune responses.…”

Surgical Strategies for Recurrent Hepatocellular Carcinoma after Resection: A Review of Current Evidence

“…In the last decade, increasing attention has been drawn to IHR patterns [32][33][34], as two different events have been described with distinct prognostic significances [14,35,36].…”