Moving towards personalised therapy in patients with hepatocellular carcinoma: the role of the microenvironment

Abstract

The goal of personalised therapy based on hepatocellular carcinoma (HCC) molecular characteristics is still beyond our grasp. Systemic treatments show poor efficacy, mainly because of the great heterogeneity of the tumour. Indeed, differences in aetiology, disease stage and biochemical composition of the fibrotic liver make cirrhosis itself a highly dyshomogeneous disease. Cancer cells grow in a cirrhotic microenvironment, interacting with stromal cells and engaging matrix components that differ from patient to patient, hampering the development of drugs to treat all patients. Growing evidence suggests a role for the cross-talk between HCC and the host stroma in driving disease progression and hence prognosis and survival. Many efforts have been devoted to identifying genes responsible for good or bad prognosis, but no study has yet proven helpful in guiding therapeutic choices and management over time, also taking into account the development of drug resistance. The questions of what to target and in which patient are still unsolved. In the personalised therapy scenario, the patient rather than the disease becomes the target of the therapy. However, this still requires an evidence-based medical approach. Herein, we will discuss how individual differences in terms of quality and quantity of the tissue microenvironment components affect progression of HCC. Then, we will highlight potential druggable pathways, also considering ongoing clinical trials. The development of biomarkers will be discussed in the light of new experimental research conducted with the aim of moving towards personalised therapy in patients with HCC.

NRAGE promotes the malignant phenotype of hepatocellular carcinoma

“…An important strategy to improve patient outcome involves the identification of disease risk factors and the maintenance of vigilant surveillance of high-risk individuals to allow for recognition of the disease at a stage that is responsive to treatment with curative intent. Therefore, it is fundamental that high-risk groups are identified, followed by successful implementation of a surveillance program and recall protocol following any abnormal findings (5)(6)(7)(8). Progress has been made in identifying molecular markers for the initiation and progression of HCC that will likely increase the rate of early and potentially life-saving diagnoses (9)(10)(11)(12).…”

“…Progress has been made in identifying molecular markers for the initiation and progression of HCC that will likely increase the rate of early and potentially life-saving diagnoses (9)(10)(11)(12). The expanding amount of knowledge regarding the molecular foundations of HCC makes it increasingly clear that successful therapy requires treatment tailored to the individual patient (8).…”

Statin Use and Survival with Early-Stage Hepatocellular Carcinoma

“…It was not reported whether the previous clinical trial had excluded patients with a history of statin use, but based on the younger age distribution, prior statin use was likely lower (12). HCC is known to be a highly heterogeneous cancer by etiology, molecular signature, and microenvironmental characteristics (16)(17)(18)(19), with metastatic HCC manifesting a different molecular and immune signature from non-metastatic HCC. It is possible that statins have a stronger impact on certain molecular subtypes represented in advanced HCC, although it is yet unknown what signatures would render a tumor more responsive to statins.…”

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“…41 Many groups have developed staging systems to evaluate patients with HCC, including the Chinese University Prognostic Index (CUPI) and the Japanese Integrated Staging System (JISS) score, which are widely used in Asia, and the American Joint Committee on Cancer (AJCC), the tumor-node-metastasis (TNM) staging system, the BCLC staging system, and the Cancer of the Liver Italian Program (CLIP) staging system used in the West. All systems include an assessment of tumor stage, and most also include liver function.…”