The liver is the most common metastatic site in colorectal cancer (CRC) patients. Indeed, 25–30% of the cases develop colorectal liver metastasis (CLM), showing an extremely poor 5-year survival rate and resistance to conventional anticancer therapies. Tumor-associated macrophages (TAMs) provide a nurturing microenvironment for CRC metastasis, promoting epithelial-to-mesenchymal transition (EMT) through the TGF-β signaling pathway, thus driving tumor cells to acquire mesenchymal properties that allow them to migrate from the primary tumor and invade the new metastatic site. EMT is known to contribute to the disruption of blood vessel integrity and the generation of circulating tumor cells (CTCs), thus being closely related to high metastatic potential in numerous solid cancers. Despite the fact that it is well-recognized that the crosstalk between tumor cells and the inflammatory microenvironment is crucial in the EMT process, the association between the EMT and the role of TAMs is still poorly understood. In this review, we elaborated on the role that TAMs exert in the induction of EMT during CLM development. Since TAMs are the major source of TGF-β in the liver, we also focused on novel insights into their role in TGF-β-induced EMT.

Cholangiocarcinoma (CCA) is a primary liver tumour characterised by a poor prognosis and limited therapeutic options. Available 3D human CCA models fail to faithfully recapitulate the tumour niche. We aimed to develop an innovative patient-specific CCA-on-chip platform. A CCA tumour microenvironment was recapitulated on a microfluidic three-channel chip using primary CCA cells, cancer-associated fibroblasts (CAFs), endothelial cells, and T cells isolated from CCA specimens (n = 6). CAF and CCA cells were co-cultured in the central channel, flanked by endothelial cells in one lateral channel, recreating a tubular structure. An extensive characterisation of this platform was carried out to investigate its diffusion ability, hydrogel properties, and changes in matrix composition. Cell phenotype and functional properties were assessed. Primary cells seeded on the microfluidic device were shown to reproduce the architectural structure and maintain the original phenotype and functional properties. The tumour niche underwent a deep remodelling in the 3D device, with an increase in hydrogel stiffness and extracellular matrix deposition, mimicking in vivo CCA characteristics. T cells were incorporated into the device to assess its reliability for immune cell interaction studies. Higher T cell migration was observed using cells from patients with highly infiltrated tumours. Finally, the drug trial showed the ability of the device to recapitulate different drug responses based on patient characteristics. We presented a 3D CCA platform that integrates the major non-immune components of the tumour microenvironment and the T cell infiltrate, reflecting the CCA niche. This CCA-on-chip represents a reliable patient-specific 3D platform that will be of help to further elucidate the biological mechanisms involved in CCA and provide an efficient tool for personalised drug testing. An innovative patient-specific cholangiocarcinoma (CCA)-on-chip platform was successfully developed, integrating the major components of the tumour microenvironment (tumour cells, cancer-associated fibroblasts, endothelial cells, and immune infiltrate) and faithfully mimicking the CCA niche. This CCA-on-chip represents a powerful tool for unravelling disease-associated cellular mechanisms in CCA and provides an efficient tool for personalised drug testing.

Introduction: Tumor-associated macrophages (TAMs) are key components of a tumoral microenvironment and have been shown to impact prognosis in different cancers. Previously reported data showed that TAM morphology correlates with prognosis in colorectal liver metastases (CLMs) after hepatectomy, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger ones (L-TAMs). This study aims to externally validate this finding. Material and methods: The external cohort consisted of 84 formalin-fixed and paraffin-embedded surgical samples of CLMs and peritumoral tissue. Two-micrometer-section slides were obtained; the area and perimeter of 21 macrophages in each slide were recorded. The endpoints were TAMs morphometrics and their prognostic significance in relation to disease-free survival (DFS). Results: The average macrophage perimeter was 71.5±14.1 μm whilst the average area was 217.7±67.8 μm². At univariate analysis, the TAM area demonstrated a statistically significant association with DFS (P=0.0006). Optimal area cutoff value was obtained, showing a sensitivity and specificity of 92 and 56%, respectively. S-TAMs and L-TAMs were associated with 3-year DFS rates of 60 and 8.5%, respectively (P<0.001). Multivariate analysis confirmed the predictive role of TAM area for DFS [hazard ratio (HR)=5.03; 95% CI=1.70–14.94; P=0.003]. Moreover, in a subset of patients (n=12) characterized by unfavorable (n=6, recurrence within 3 months) or favorable (n=6, no recurrence after 48 months) prognosis, TAMs showed a different distribution: L-TAMs were more abundant and closer to the tumor invasive margin in patients that encountered early recurrence and tended to cluster in foci significantly larger (P=0.02). Conclusions: This external validation confirms that morphometric characterization of TAMs can serve as a simple readout of their diversity and allows to reliably stratify patient outcomes and predict disease recurrence after hepatectomy for CLMs.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and both liver resection and liver transplantation are considered potentially curative options. However, high recurrence rates affect the prognosis depending both on the primary HCC pathology characteristics or on the type and time of the relapse. While great attention has been usually posted on treatment algorithms for the first HCC, treatment algorithms for recurrent HCC (rHCC) are lacking. In these cases, surgery still represents a curative option with both redo hepatectomy and/or salvage liver transplantation, which are considered valid treatments in selected patients. In the current era of personalised medicine with promises of new systemic-targeted immuno-chemotherapies, we wished to perform a narrative review of the literature on the role of surgical strategies for rHCC.

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.