Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5 + compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.
Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with 111 In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation. Al most all nanocarriers, including liposomes (1), and many other anticancer drugs rely on the enhanced permeability and retention (EPR) effect for accumulation in tumor tissue. The EPR effect is defined as the process of extravasation of large molecules from leaky tumor vasculature, leading to accumulation in tumor tissue (2). The EPR effect is dependent on many biological parameters, with the development of the abnormal tumor vasculature playing a major role, although other parameters such as the composition of the surrounding stroma, absence of functional lymphatics, and presence of tumor infiltrating macrophages also play an important role (3). Abnormally upregulated growth factors affect the vasculature of the tumor (4) and lead to large endothelial junctions at the luminal surface, resulting in a leaky vasculature (5). In addition, vessels lack smooth muscle cell layers and supporting cells (6), and the fast recruitment of blood vessels results in tumor neovasculature that is not hierarchically organized, causing a heterogeneous spatial distribution (4,7,8). Finally, tumors overexpress many permeability-enhancing factors, which contribute to an enhanced EPR effect (9). These observations suggest that most tumors may be susceptible to nanoparticle treatment, but thus far such particles show only a limited effect in vivo due to various barriers such as the mononuclear phagocyte system, extracellular matrix, low pH, low oxygenation, and high interstitial fluid pressure (10-12)....
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