Hepatitis B virus X protein and TGF-ß: partners in the carcinogenic journey of hepatocellular carcinoma.

Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-ß (TGF-ß) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-ß has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-ß interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-ß in HCC occurrence and development.

Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution.

The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.

Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle.

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.

Dysregulation of delta Np63 alpha in squamous cell carcinoma and its therapeutic targeting.

The gene p63 has two isoforms -a full length transactivated isoform (TA) p63 and an amino-terminally truncated isoform, ∆Np63. DeltaNp63 alpha (∆Np63α) is the predominant splice variant of the isoform, ∆Np63 and is expressed in the basal layer of stratified epithelia. ∆Np63α that is normally essential for the epithelial lineage maintenance may be dysregulated in squamous cell carcinomas (SCCs). The pro-tumorigenic or antitumorigenic role of ∆Np63 is a highly contentious arena. ∆Np63α may act as a double-edged sword. It may either promote tumor progression, epithelial-mesenchymal transition, migration, chemoresistance, and immune-inflammatory responses, or inhibit the aforementioned phenomena depending upon cell type and tumor microenvironment. Several signaling pathways, transforming growth factor-ß, Wnt and Notch, as well as epigenetic alterations involving microRNAs, and long noncoding RNAs are regulated by ∆Np63α. This review has attempted to provide an in-depth insight into the role of ∆Np63α in the development of SCCs during different stages of tumor formation and how it may be targeted for therapeutic implications.

Roles of extracellular vesicles in glioblastoma: foes, friends and informers.

Glioblastoma (GB) tumors are one of the most insidious cancers which take over the brain and defy therapy. Over time and in response to treatment the tumor and the brain cells in the tumor microenvironment (TME) undergo many genetic/epigenetic driven changes in their phenotypes and this is reflected in the cellular contents within the extracellular vesicles (EVs) they produce. With the result that some EVs try to subdue the tumor (friends of the brain), while others participate in the glioblastoma takeover (foes of the brain) in a dynamic and ever changing process. Monitoring the contents of these EVs in biofluids can inform decisions based on GB status to guide therapeutic intervention. This review covers primarily recent research describing the different cell types in the brain, as well as the tumor cells, which participate in this EV deluge. This includes EVs produced by the tumor which manipulate the transcriptome of normal cells in their environment in support of tumor growth (foes), as well as responses of normal cells which try to restrict tumor growth and invasion, including traveling to cervical lymph nodes to present tumor neo-antigens to dendritic cells (DCs). In addition EVs released by tumors into biofluids can report on the status of living tumor cells via their cargo and thus serving as biomarkers. However, EVs released by tumor cells and their influence on normal cells in the tumor microenvironment is a major factor in immune suppression and coercion of normal brain cells to join the GB "band wagon". Efforts are being made to deploy EVs as therapeutic vehicles for drugs and small inhibitory RNAs. Increasing knowledge about EVs in the TME is being utilized to track tumor progression and response to therapy and even to weaponize EVs to fight the tumor.

Emerging role of mesenchymal stromal cells in gynecologic cancer therapy.

Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.

"Pulsed Hypoxia" Gradually Reprograms Breast Cancer Fibroblasts into Pro-Tumorigenic Cells via Mesenchymal-Epithelial Transition.

Hypoxia arises in most growing solid tumors and can lead to pleotropic effects that potentially increase tumor aggressiveness and resistance to therapy through regulation of the expression of genes associated with the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). The main goal of the current work was to obtain and investigate the intermediate phenotype of tumor cells undergoing the hypoxia-dependent transition from fibroblast to epithelial morphology. Primary breast cancer fibroblasts BrC4f, being cancer-associated fibroblasts, were subjected to one or two rounds of "pulsed hypoxia" (PH). PH induced transformation of fibroblast-shaped cells to semi-epithelial cells. Western blot analysis, fluorescent microscopy and flow cytometry of transformed cells demonstrated the decrease in the mesenchymal markers vimentin and N-cad and an increase in the epithelial marker E-cad. These cells kept mesenchymal markers αSMA and S100A4 and high ALDH activity. Real-time PCR data of the cells after one (BrC4f_Hyp1) and two (BrC4f_Hyp2) rounds of PH showed consistent up-regulation of TWIST1 gene as an early response and ZEB1/2 and SLUG transcriptional activity as a subsequent response. Reversion of BrC4f_Hyp2 cells to normoxia conditions converted them to epithelial-like cells (BrC4e) with decreased expression of EMT genes and up-regulation of MET-related OVOL2 and c-MYC genes. Transplantation of BrC4f and BrC4f_Hyp2 cells into SCID mice showed the acceleration of tumor growth up to 61.6% for BrC4f_Hyp2 cells. To summarize, rounds of PH imitate the MET process of tumorigenesis in which cancer-associated fibroblasts pass through intermediate stages and become more aggressive epithelial-like tumor cells.

IL4I1 and tryptophan metabolites enhance AHR signals to facilitate colorectal cancer progression and immunosuppression.

OBJECTIVE: The molecular mechanisms underlying tumor progression and drug resistance in colorectal cancer remain to be fully understood. Recent studies have reported a pro-tumorigenic role of an amino acid oxidase named interleukin-4-induced-1 (IL4I1). Here, we investigate the role and molecular mechanism of IL4I1 in colorectal cancer. METHODS: We employed bioinformatics analysis and experimental validation by using clinical samples and a variety of cell-based assays, including western blot, Transwell assay, patient-derived organoid culture, Immunofluorescence assay, T cell cytotoxicity assay, and flow cytometry. RESULTS: Bioinformatics analysis showed a higher IL4I1 expression in colorectal cancer tissues than in normal tissues. In vitro overexpression of IL4I1 enhanced the proliferation, migration, and invasion of colorectal cancer cells. In addition, deprivation of Tryptophan (Trp) in cultural medium diminished the oncogenic effect of IL4I1. Furthermore, we observed a positive correlation of IL4I1 and AHR expression in the TCGA database of colorectal cancer. We also detected an enhanced cytoplasmic expression and nuclear translocation of Aryl hydrocarbon receptor (AHR). Moreover, IL4I1 overexpression suppressed the cytolytic killing of tumor cells and enhanced T cell exhaustion. Finally, in the organoid culture model, we found that immunotherapy and SR-1 combination treatment could induce higher level of apoptosis than did the immunotherapy or SR-1 treatment alone. CONCLUSION: we demonstrated that IL4I1 facilitated colorectal cancer progression and immunosuppression through tryptophan metabolism dependent on AHR activation.

Function and therapeutic development of exosomes for cancer therapy.

Exosomes are extracellular vesicles, 50-150 nm in diameter, released by most cells. Exosomes contain several intracellular components, including DNA, RNA, and proteins, which reflect the parent cell's status and contribute to intercellular communication. Cancers are associated with high morbidity and mortality rates worldwide. Owing to a high survival rate, cancer treatment by immune modulation of the tumor microenvironment has recently received a lot of attention. Exosomes' role in immunological control is also being studied extensively. Exosomes play a role in cancer-immune cell communication. Through intracellular communication, exosomes promote tumor growth, metastasis, angiogenesis, and drug resistance. In addition, innate immune cell-derived exosomes and adaptive immune cell exosomes have an anti-tumorigenic activity. Exosome-related tumor microenvironment drugs are being developed, including inhibitors of exosomal release, tumor-derived exosomes, and immune cell-derived exosome engineering, although there are still some obstacles to overcome. We describe in this review the significance of exosomes in the tumor microenvironment. We also summarize current studies on anticancer immune drug development and the challenges in developing exosome-related drugs.

The Bright and the Dark Side of TGF-ß Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor ß (TGF-ß) signaling pathway. The regulatory cytokine TGF-ß and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-ß signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-ß functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial-mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-ß signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-ß signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-ß signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.

The role of NLRP3 inflammasome in digestive system malignancy.

Digestive system malignancies, the most common types of cancer and a major cause of death in the worldwide, are generally characterized by high morbidity, insidious symptoms and poor prognosis. NLRP3 inflammasome, the most studied inflammasome member, is considered to be crucial in tumorigenesis. In this paper, we reviewed its pro-tumorigenic and anti-tumorigenic properties in different types of digestive system malignancy depending on the types of cells, tissues and organs involved, which would provide promising avenue for exploring new anti-cancer therapies.

The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine.

Carbon monoxide (CO) is now well recognized a pivotal endogenous signaling molecule in mammalian lives. The proof-of-concept employing chemical carriers of exogenous CO as prodrugs for CO release, also known as CO-releasing molecules (CO-RMs), has been appreciated. The major advantage of CO-RMs is that they are able to deliver CO to the target sites in a controlled manner. There is an increasing body of experimental studies suggesting the therapeutic potentials of CO and CO-RMs in different cancer models. This review firstly presents a short but crucial view concerning the characteristics of CO and CO-RMs. Then, the anticancer activities of CO-RMs that target many cancer hallmarks, mainly proliferation, apoptosis, angiogenesis, and invasion and metastasis, are discussed. However, their anticancer activities are varying and cell-type specific. The aerobic metabolism of molecular oxygen inevitably generates various oxygen-containing reactive metabolites termed reactive oxygen species (ROS) which play important roles in both physiology and pathophysiology. Although ROS act as a double-edged sword in cancer, both sides of which may potentially have been exploited for therapeutic benefits. The main focus of the present review is thus to identify the possible signaling network by which CO-RMs can exert their anticancer actions, where ROS play the central role. Another important issue concerning the potential effect of CO-RMs on the aerobic glycolysis (the Warburg effect) which is a feature of cancer metabolic reprogramming is given before the conclusion with future prospects on the challenges of developing CO-RMs into clinically pharmaceutical candidates in cancer therapy.

Mesenchymal stem cells in glioblastoma therapy and progression: How one cell does it all.

Mesenchymal stem cells (MSCs) are among the most investigated and applied somatic stem cells in experimental therapies for the regeneration of damaged tissues. Moreover, as it was recently postulated, MSCs may demonstrate anti-tumor properties. Glioblastoma (GBM) is a grade IV central nervous system tumor with no available effective therapy and an inevitably fatal prognosis. Experimental studies utilizing MSCs in GBM treatment resulted in numerous controversies. Native MSCs were shown to exert anti-GBM activity by controlling angiogenesis, regulating cell cycle, and inducing apoptosis. They also were used as sensitizing factors and vehicles delivering various anti-cancer compounds. On the other hand, some experiments revealed significant risks related to MSC-based therapies for GBM, such as enhancement of tumor cell proliferation, invasion, and aggressiveness. The following review elaborates on all mentioned contradictory data and provides a realistic, current clinical perspective on MSCs' potential in GBM treatment.

Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment.

NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol+++ cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol+++. We demonstrated that Hiltonol+++ kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome c, (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2'5' oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol+++ cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.

Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors.

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

Pro-tumorigenic functions of macrophages at the primary, invasive and metastatic tumor site.

The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.

Water extract from Euglena gracilis prevents lung carcinoma growth in mice by attenuation of the myeloid-derived cell population.

The partially purified water extract from Euglena gracilis (EWE) was evaluated for its antitumor and immunomodulatory effects in cell cultures and in a mouse orthotopic lung carcinoma allograft model. In two-dimensional cell culture, the EWE treatment inhibited cell growth of both murine Lewis lung carcinoma (LLC) and human lung carcinoma cells (A549 and H1299) in a dose- and time-dependent manner. In contrast, the growth of mouse bone marrow cells (BMCs), but not mouse splenocytes (SPLs), was stimulated by the treatment with EWE. In three-dimensional spheroid culture, spheroid growth of LLC cells was significantly attenuated by EWE treatment. In a mouse LLC orthotopic allograft model, pretreatment with EWE (150-200 mg/kg/day, via drinking water) three weeks prior to the LLC cell inoculation, but not post-treatment after LLC cell inoculation, significantly attenuated the growth of LLC tumors in immunocompetent syngeneic mouse lung. This tumor growth attenuation coincided with a significant decrease in the population of myeloid-derived cells, primarily neutrophils. Flow cytometric analysis revealed that the EWE treatment significantly attenuated growth of granulocytic myeloid-derived suppressor cells (gMDSC) in BMCs and that this decrease was due to induction of gMDSC-specific apoptosis and differentiation of monocytic MDSCs (mMDSC) to macrophages. The present study provides evidence that EWE pretreatment inhibits lung carcinoma growth mainly by stimulating host antitumor immunity through attenuation of growth of gMDSCs and decreasing the number of peripheral granulocytes. This study suggests that the partially purified extract derived from Euglena gracilis contains significant bioactive materials that prevent lung carcinoma growth.

Fibroblasts in the Tumor Microenvironment.

The implications of a tumor microenvironment in cancer initiation and progression have drawn interest in recent years. Within the tumor stroma, fibroblasts represent a predominant cell type and are responsible for the majority of extracellular components within the tumor microenvironment, such as matrix and soluble factors. A switch from quiescent fibroblasts to cancer-associated fibroblasts triggers a large variety of pro-tumorigenic signals that support tumor progression and shape the surrounding pathological stroma, with the remodeling of tissue architecture and repression of the local immune response. The heterogeneous nature of cancer-associated fibroblasts and their multiple functions are subject of active research as they could represent promising targets for cutting-edge therapeutic approaches to cancer and the tumor microenvironment.

Interferon α in cancer immunoediting: From elimination to escape.

Interferon α (IFNα) is a cytokine that mediates diverse immune responses to tumours. It is the oldest immune-based oncologic drug and has been widely used to treat various malignancies in humans. Yet, the use of IFNα in cancer therapy has only resulted in limited success and even led to worse clinical outcomes under certain instances. The emergence of the cancer immunoediting concept-which implicates the host immune system in promoting tumour growth-recapitulates the need to evaluate the immune functions of IFNα. This review proposes that IFNα has dual opposing roles in cancer development based on the mutational status of its signalling components, which determines the expression of anti- or pro-tumorigenic IFN-stimulated genes (ISGs). This duality may translate into new applications of IFNα in cancer immunotherapy.

B7-H3 Immune Checkpoint Protein in Human Cancer.

B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.