Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution.

Targeted siRNA nanotherapeutics against breast and ovarian metastatic cancer: a comprehensive review of the literature

Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug delivery strategies using siRNA therapeutics.

Pulmonary Delivery of Engineered Exosomes to Suppress Postoperative Melanoma Lung Metastasis through Preventing Premetastatic Niche Formation

Premetastatic niche (PMN) is a prerequisite for initiation of tumor metastasis. Targeting prevention of PMN formation in distant organs is becoming a promising strategy to suppress metastasis of primary tumor. Based on “organotropic metastasis”, melanoma tends to metastasize to lungs, where granulocytic myeloid-derived suppressor cells (G-MDSCs) recruitment in lungs significantly contributes to the PMN formation. Herein, functional exosomes (GExoI) were designed to present pulmonary targeting peptide GFE1 on the membrane and load PI3Kγ inhibitor (IPI549) inside, aiming at suppressing postoperative lung metastasis of melanoma. In postoperative mice model, intravenously injected GExoI could significantly accumulate in lungs and release IPI549 to block G-MDSCs recruitment through interfering with CXCLs/CXCR2/PI3Kγ signaling. The increased percentages of CD4+ T cells and CD8+ T cells in lungs could transform microenvironment from immunosuppression to immunostimulation, leading to metastasis inhibition. This study suggests an effective anti-metastasis strategy of targeting prevention of PMN formation through specifically blocking G-MDSCs recruitment.

Breast Cancer Cells Metastasize to the Tissue-Engineered Premetastatic Niche by Using an Osteoid-Formed Polycaprolactone/Nanohydroxyapatite Scaffold

It has been deemed that the premetastatic niche (PMN) plays a critical role in facilitating bone metastasis of breast cancer cells. Tissue engineering scaffolds provide an advantageous environment to promote osteogenesis that may mimic the bony premetastatic niches (BPMNs). In this study, human mesenchymal stem cells (hMSCs) were seeded onto designed polycaprolactone/nanohydroxyapatite (PCL-nHA) scaffolds for osteogenic differentiation. Subsequently, a coculture system was used to establish the tissue-engineered BPMNs by culturing breast cancer cells, hMSCs, and osteoid-formed PCL-nHA scaffolds. Afterwards, a migration assay was used to investigate the recruitment of MDA-MB-231, MCF-7, and MDA-MB-453 cells to the BPMNs’ supernatants. The cancer stem cell (CSC) properties of these migrated cells were investigated by flow cytometry. Our results showed that the mRNA expression levels of alkaline phosphatase (ALP), Osterix, runt-related transcription factor 2 (Runx2), and collagen type I alpha 1 (COL1A1) on the PCL-nHA scaffolds were dramatically increased compared to the PCL scaffolds on days 11, 18, and 32. The expression of CXCL12 in these BPMNs was increased gradually over coculturing time, and it may be a feasible marker for BPMNs. Furthermore, migration analysis results showed that the higher maturation of BPMNs collectively contributed to the creation of a more favorable niched site for the cancerous invasion. The subpopulation of breast cancer stem cells (BCSCs) was more likely to migrate to fertile BPMNs. The proportion of BCSCs in metastatic MDA-MB-231, MCF-7, and MDA-MB-453 cells were increased by approximately 63.47%, 149.48%, and 127.60%. The current study demonstrated that a designed tissue engineering scaffold can provide a novel method to create a bone-mimicking environment that serves as a useable platform to recapitulate the BPMNs and help interrogate the scheme of bone metastasis by breast cancer.

Neutrophil Extracellular Traps (NETs) in Cancer Metastasis

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

Radiogenomics: Hunting Down Liver Metastasis in Colorectal Cancer Patients

Radiomics is a developing new discipline that analyzes conventional medical images to extract quantifiable data that can be mined for new biomarkers that show the biology of pathological processes at microscopic levels. These data can be converted into image-based signatures to improve diagnostic, prognostic and predictive accuracy in cancer patients. The combination of radiomics and molecular data, called radiogenomics, has clear implications for cancer patients’ management. Though some studies have focused on radiogenomics signatures in hepatocellular carcinoma patients, only a few have examined colorectal cancer metastatic lesions in the liver. Moreover, the need to differentiate between liver lesions is fundamental for accurate diagnosis and treatment. In this review, we summarize the knowledge gained from radiomics and radiogenomics studies in hepatic metastatic colorectal cancer patients and their use in early diagnosis, response assessment and treatment decisions. We also investigate their value as possible prognostic biomarkers. In addition, the great potential of image mining to provide a comprehensive view of liver niche formation is examined thoroughly. Finally, new challenges and current limitations for the early detection of the liver premetastatic niche, based on radiomics and radiogenomics, are also discussed.

Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis

BackgroundNeutrophils-linked premetastatic niche plays a key role in tumor metastasis, but not much is known about the heterogeneity and diverse role of neutrophils in niche formation. Our study focuses on the existence and biological function of a rarely delved subset of neutrophils, named as tumor-associated aged neutrophils (Naged, CXCR4+CD62Llow), involved in premetastatic niche formation during breast cancer metastasis.MethodsWe explored the distributions of Naged in 206 patients and mice models (4T1 and MMTV-PyMT) by flow cytometry. The ability of Naged to form neutrophil extracellular traps (NETs) and promote tumor metastasis in patients and mice was determined by polychromatic immunohistochemistry, scanning electron microscopy and real-time video detection. Furthermore, the differences among tumor-associated Naged, Non-Naged and inflammation-associated aged neutrophils were compared by transcriptome, the biological characteristics of Naged were comprehensively analyzed from the perspectives of morphology, the metabolic capacity and mitochondrial function were investigated by Seahorse, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and transmission electron microscopy (TEM). Finally, 120 patients’ sample were applied to confirm the acceleration of Naged formation through secreted NAMPT, and the importance of blocking this pathway in mice was evaluated.ResultsWe find that Naged accumulate in the lung premetastatic niche at early stage of breast tumorigenesis in multiple mice models and also exist in peripheral blood and metastatic lung of patients with breast cancer. Naged exhibit distinct cell marker and morphological feature of oversegmented nuclei. Further transcriptome reveals that Naged are completely different from those of Non-Aged or inflammation-associated aged neutrophils and illustrates that the key transcription factor SIRT1 in Naged is the core to maintain their lifespan via mitophagy for their function. The responsible mechanism is that SIRT1 can induce the opening of mitochondrial permeability transition pore channels to release mitochondrial DNA and lead to the mitochondria-dependent vital NETs formation, rather than traditional Cit-Histone H3 dependent fatal-NETs. Further mechanically investigation found tumor derived NAMPT could induce Naged formation. Additionally, therapeutic interventions of Naged and its formation-linked pathways could effectively decrease breast cancer lung metastasis.ConclusionsNaged exerts a vital role in breast cancer lung metastasis, and strategies targeting SIRT1-Naged-NETs axis show promise for translational application.

Extracellular Vesicles in Bone Tumors: How to Seed in the Surroundings Molecular Information for Malignant Transformation and Progression

Bone is a very dynamic tissue hosting different cell types whose functions are regulated by a plethora of membrane-bound and soluble molecules. Intercellular communication was recently demonstrated to be also sustained by the exchange of extracellular vesicles (EVs). These are cell-derived nanosized structures shuttling biologically active molecules, such as nucleic acids and proteins. The bone microenvironment is a preferential site of primary and metastatic tumors, in which cancer cells find a fertile soil to “seed and blossom”. Nowadays, many oncogenic processes are recognized to be sustained by EVs. For example, EVs can directly fuel the vicious cycle in the bone/bone marrow microenvironment. EVs create a favourable environment for tumor growth by affecting osteoblasts, osteoclasts, osteocytes, adipocytes, leukocytes, and endothelial cells. At the same time other crucial tumor-mediated events, such as the premetastatic niche formation, tumor cell dormancy, as well as drug resistance, have been described to be fostered by tumor-derived EVs. In this review, we will discuss the main body of literature describing how the cancer cells use the EVs for their growth into the bone and for educating the bone microenvironment to host metastases.

Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer

Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.