Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, ...which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.
Angiogenesis plays an instrumental role in the modulation of adipose tissue mass and metabolism. Targeting adipose vasculature provides an outstanding opportunity for treatment of obesity and ...metabolic disorders. Here, we report the physiological functions of VEGFR1 in the modulation of adipose angiogenesis, obesity, and global metabolism. Pharmacological inhibition and genetic deletion of endothelial VEGFR1 augmented adipose angiogenesis and browning of subcutaneous white adipose tissue, leading to elevated thermogenesis. In a diet-induced obesity model, endothelial-VEGFR1 deficiency demonstrated a potent anti-obesity effect by improving global metabolism. Along with metabolic changes, fatty liver and insulin sensitivity were also markedly improved in VEGFR1-deficient high fat diet (HFD)-fed mice. Together, our data indicate that targeting of VEGFR1 provides an exciting new opportunity for treatment of obesity and metabolic diseases, such as liver steatosis and type 2 diabetes.
Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe ...AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.
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•Tumors grown in adipose tissues tend to be AAD resistant•AAD induces hypoxia and limits glucose supply and induces lipolysis•Tumor cells switch from glycolysis to FAO metabolism upon AAD treatment•Dual targeting angiogenesis and FAO increases anti-tumor activity
Antiangiogenic drug (AAD) resistance is a frequent problem in cancer patients. Iwamoto et al. show that vascularization is not a limiting factor. Instead, AAD triggered a lipid-dependent metabolic reprogramming, resulting in increased free fatty acid and cancer cell proliferation. Inhibition of fatty acid oxidation enhanced the therapeutic efficacy of AAD.
CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate‐cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species ...(ROS). This mechanism confers ROS resistance to CSC and CD44v9‐expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing ROS‐mediated apoptosis. Twenty non‐pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD44v9 and xCT expression. Human HCC cell lines HAK‐1A and HAK‐1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD44v9 positivity was significantly higher in HAIC‐treated tissues (5/7) than in non‐pretreated tissues (2/30), suggesting the involvement of CD44v9 in the resistance to HAIC. xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD44v9‐harboring HAK‐1B cells through ROS‐mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS‐mediated apoptosis in CDDP‐treated HCC cells, in which the CD44v9‐xCT system functioned. As CD44v9 is typically expressed in HAIC‐resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance.
This study is the first to show high expression of CD44v9, a cancer stem cell marker, in chemoresistant hepatocellular carcinoma cells, which were previously exposed to chemotherapeutic agents through hepatic arterial infusion chemoembolization.
Metabolic reprograming is crucial in the proliferation of hepatocellular carcinoma (HCC). Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, affects various metabolisms. We ...investigated the effects of CANA on proliferation and metabolic reprograming of HCC cell lines using multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT).
The cells were counted 72 hours after treatment with CANA (10 μM; n = 5) or dimethyl sulfoxide (control CON; n = 5) in Hep3B and Huh7 cells. In Hep3B cells, metabolomics and iMPAQT were used to evaluate the levels of metabolites and metabolic enzymes in the CANA and CON groups (each n = 5) 48 hours after treatment.
Seventy-two hours after treatment, the number of cells in the CANA group was significantly decreased compared to that in the CON group in Hep3B and Huh7 cells. On multi-omics analysis, there was a significant difference in the levels of 85 metabolites and 68 metabolic enzymes between the CANA and CON groups. For instance, CANA significantly downregulated ATP synthase F1 subunit alpha, a mitochondrial electron transport system protein (CON 297.28±20.63 vs. CANA 251.83±22.83 fmol/10 μg protein; P = 0.0183). CANA also significantly upregulated 3-hydroxybutyrate, a beta-oxidation metabolite (CON 530±14 vs. CANA 854±68 arbitrary units; P<0.001). Moreover, CANA significantly downregulated nucleoside diphosphate kinase 1 (CON 110.30±11.37 vs. CANA 89.14±8.39 fmol/10 μg protein; P = 0.0172).
We found that CANA suppressed the proliferation of HCC cells through alterations in mitochondrial oxidative phosphorylation metabolism, fatty acid metabolism, and purine and pyrimidine metabolism. Thus, CANA may suppress the proliferation of HCC by regulating metabolic reprograming.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recently, treatments for unresectable hepatocellular carcinoma (HCC) have undergone remarkable development. Various systemic chemotherapy drugs have been approved and are recommended by clinical ...guidelines worldwide. Although systemic treatments are effective and contribute to prolonged patient survival, their effects are unsatisfactory for some specific tumor conditions, such as macrovascular invasion. Hepatic arterial infusion chemotherapy (HAIC) is a traditional treatment for advanced HCC. As yet, there is no worldwide consensus recommending HAIC because no high-quality clinical trials have demonstrated its survival benefit. However, clinical evidence is gradually accumulating that shows its survival benefit, and it is recognized as an effective locoregional treatment for advanced HCC. Several HAIC regimens have been reported, including cisplatin monotherapy, cisplatin plus 5-fluorouracil (low-dose FP), lipiodol-suspended FP, and an oxaliplatin-based regimen. We have entered an era of chemo-diversity in the treatment of advanced HCC. This review aimed to clarify the relevance of HAIC in the era of chemo-diversity. We propose a multidisciplinary therapeutic strategy combining locoregional HAIC treatment with sequential drug therapy, with the aim of becoming cancer-free through conversion therapy.
Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between ...perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.
The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown ...of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A–null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk ⁻/⁻ mice and mice treated with anti–VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.
Significance Cancer metastasis is responsible for a majority of the mortality in cancer patients and involves complex interactions, modulated by various factors and cytokines, between malignant and host cells. Vascular structures in solid tumors are crucial for cancer cell intravasation into the circulation. Our present work shows that VEGF-B produced by tumor cells significantly remodels tumor microvasculature, leading to leaky vascular networks that are highly permissive for tumor cell invasion. VEGF-B–promoted cancer metastasis occurs through a VEGF-A–independent mechanism. Thus, inhibition of VEGF-B should be considered an independent approach for the development of new drugs for the treatment of cancer invasion and metastasis. VEGF-B also may be considered as an independent prognostic marker for cancer metastasis.
In this work, a technique to reduce the acoustic velocity of incredible high-performance surface acoustic wave (I.H.P. SAW) using Al/Pt electrodes keeping other important characteristics such as ...fractional bandwidth and quality factor is proposed. First, using a finite element method simulator, variations of the acoustic velocity and the fractional bandwidth of the I.H.P. SAW with the Pt electrode thickness, thicknesses of LiTaO3 (LT) and SiO2 layers in a substrate, and the cut angle of a LT layer are estimated. And then, to confirm the validity of the estimation results, several one-port SAW resonators with various thickness combinations of Al, Pt, LT, and SiO2 layers are fabricated and their characteristics are evaluated. The evaluation results show that the acoustic velocity of the I.H.P. SAW is successfully reduced keeping the bandwidth, the quality factor, and the temperature characteristics.
Doublecortin-like kinase 1 (DCLK1), a marker for intestinal and pancreatic cancer stem cells, is highly expressed in neuroblastomas. This study was conducted to assess DCLK1 expression levels in ...pancreatic neuroendocrine tumor (PNET) tissues and to explore the roles of this molecule in clinical tissue from multiple PNET patients, cells (BON1, QGP1, and CM) and tumor xenografts. Immunohistochemically, all PNET tissues highly and diffusely expressed DCLK1 as a full-length isoform, identical to that detected in primary liver NETs. A DCLK1-overexpressing PNET cell line (QGP1-DCLK1) exhibited epithelial-mesenchymal transition (EMT)-related gene signatures, and robust upregulation of Slug (SNAI2), N-Cadherin (CDH2), and Vimentin (VIM) was validated by real-time PCR and immunoblotting. QGP1-DCLK1 cells had increased cell migration in a wound-healing assay and formed significantly larger xenograft tumors in nude mice. The factors involved in the formation of the fast-growing tumors included p-FAK (on Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1, which upon knockdown or pharmacologic inhibition of DCLK1 abolished the expression of these molecules. In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1.
Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1.
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