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-β (TGF-β) 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-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.

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- β (TGF-β) 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.

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/β-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-β) 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.

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.

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.

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-β, 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.

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.

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.
CONCLUSIONS: we demonstrated that IL4I1 facilitated colorectal cancer progression and immunosuppression through tryptophan metabolism dependent on AHR activation.

Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β 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-β 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-β 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-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β 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-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.

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.