Cancer and Metastasis Reviews

Angiogenesis is required for the continual growth of the tumor and provides a gateway for cells to escape the confines of the primary tumor. Angiogenic stimulus triggers a cascade of functional responses leading to local basement membrane dissolution, endothelial cell migration, proliferation and microvessel morphogenesis. In this commentary, we review the significance of carbohydrate-binding proteins involved in angiogenesis. The importance of carbohydrate-recognition processes to angiogenesis stems from the observation that angiogenic factors like fibroblast growth factor family and vascular endothelial growth factors bind initially to the extracellular matrix proteoglycans before binding to their cognate receptors, and some of the adhesion molecules bind to glycoconjugates present on the surface of the endothelial cells. The possible significance of these interactions will be discussed.

One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative splice variants, an attribute of the vast majority of multi-exon genes. Members of the RAS family, such as NRAS, KRAS and HRAS, all of which are of significant importance in cancer biology, are no exception. The structural and functional differences of these splice variants, particularly if they contain the canonical (and therefore routinely targeted for diagnostic purposes) hot spot mutations, pose a significant challenge for targeted therapies. We must therefore consider whether these alternative splice variants constitute a minor component as originally thought and how therapies targeting the canonical isoforms affect these alternative splice variants and their overall functions.

The presence of early disseminated tumor cells (DTC), otherwise termed micrometastases or minimal residual disease, in the bone marrow (BM), or other secondary compartments, such as the blood and the lymph nodes, is the main reason for recurrence of patients with early stage epithelial cancers after “curative” resection of the primary tumor. There is increasing evidence, that the detection of DTC in BM aspirates may provide additional and independent prognostic information and aid in the stratification of these patients for adjuvant clinical treatment. However, the clinical relevance of micrometastases has not yet been firmly established. In addition, the molecular events and interactions that prevail in early metastatic disease and determine the formation or not of overt metastases remain poorly understood. The methods currently used for the detection of micrometastatic cells include extremely sensitive immunocytochemical and molecular assays, often in conjunction with enrichment techniques for the purification of tumor cells and additional increase of their sensitivity. Nevertheless, the specificity of these methods is mostly inadequate. After the impressive advances of molecular cytogenetics, a highly accurate and global assessment of the genetic status of tumors is now possible. Therefore, the greatest challenge of our time is the application of these novel technologies for the clarification of the key molecular events that initiate metastatic spread. This will further enable us to identify the highly specific and sensitive diagnostic and prognostic markers as well as the therapeutic targets which are so urgently needed.

Recent studies suggest abnormal microRNA (miRNA) expression may have potential prognostic value in childhood acute lymphoblastic leukemia (ALL). In this systematic review, we searched different databases (PubMed, ASH, ASCO, and SIOP) for studies published from 2008 to 2018 that evaluated the prognostic impact of miRNAs in childhood ALL. We also used DIANA-miRPath v3.0 to further characterize the functional role of the significant prognostic miRNAs identified in our systematic review. Here we evaluate 15 studies with a total of 38 different miRNAs and 1545 children with B-cell ALL (B-ALL) or T-cell ALL (T-ALL) recruited over approximately 3 decades (1984–2016) with different treatment protocols and ethnicities. Out of the 15 studies examined, 14 reported 32 dysregulated miRNAs with significant prognostic impact in pediatric ALL patients. Only one Brazilian study reported no significant prognostic effect of 7 miRNAs, while the seventh miRNA (miR-100) showed prognostic significance in a Chinese study. Using DIANA-TarBase v7.0 of DIANA-miRPath v3.0, pathway enrichment analysis revealed 25 miRNAs modulated 24 molecular pathways involved in cancer development. To remove the effect of salvage therapy, 9 studies carried out multivariate cox regression analysis for both relapse-free survival and disease-free survival to develop a panel of 23 miRNAs acting as independent prognostic biomarkers. To enhance the clinical application, utility, and validity of the miRNAs discussed here, their potential prognostic value should be confirmed in larger cohort studies within different ethnicities and different ALL protocols adjusted for other contemporary validated prognostic factors in childhood ALL.

The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

Human neoplasms are heterogeneous for a variety of biological properties that include invasion and metastasis. The presence of a small subpopulation of cells with a highly metastatic phenotype has important clinical implications for diagnosis and therapy of cancer. For this reason, it is important to develop an animal model for the selection and isolation of metastatic variants from human neoplasms and for testing the metastatic potential of human tumor cells. We have implanted human renal cell carcinoma (HRCC) cells (obtained from a surgical specimen) into different organs of nude mice and then recovered the tumors and established each in culture. The 5 established lines differed in their biological-metastatic properties and had a unique karyotype, indicating that growth at different organs selects for different subpopulations of HRCC. Moreover, the HRCC did not metastasize unless they were implanted orthotopically. These findings indicate that the appropriate nude mouse model for studying the biology and therapy of HRCC must be based on the orthotopic implantation of tumor cells.

Cancer progression is facilitated by distinct mechanisms developed by cancer cells to avoid immune recognition and clearance. The clinical application of immune checkpoint blockade (ICB), via monoclonal antibodies blocking PD-1/PD-L1 and CTLA4, has achieved promising durable therapeutic response in various cancer types, including recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). HNSCC represents a rational target of ICB treatment given its relatively high mutation burden and the presence of immune infiltrates. However, the limited response rates and recent negative clinical trials data identify an urgent need for new strategies to overcome immunotherapy resistance. Preclinical studies have revealed an important contribution of epigenetic regulators in the anti-tumor immune response. Multiple components of the tumor and host immune system interaction are under epigenetic regulation, including the cancer cells themselves, cytotoxic T lymphocytes, regulatory T lymphocytes, natural killer cells, and tumor-associated macrophages. Epigenetic targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase, and methyltransferase inhibitors have demonstrated the potential to reverse immune suppression in various cancer models. The aim of this review is to summarize recent preclinical studies focused on investigating the function of epigenetic modulation in the host immune and cancer cell interface. We also provide a perspective on combining epigenetic modulation and immunotherapy in the management of HNSCC to improve outcomes—an area of great interest in future clinical studies.

The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1β as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the endothelium in vitro, and administration of IL-1 to mice increases the number of metastatic colonies and tumor growth. Importantly, reducing endogenous IL-1 activity, particularly IL-1β, with the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduces both metastasis as well as tumor burden. Inhibition of IL-1 activity prevents in vivo blood vessel formation induced by products released from hypoxic macrophages or vascular endothelial cell growth factor itself. Mice deficient in IL-1β do not form blood vessels in matrigels embedded with vascular endothelial cell growth factor or containing products of macrophages. Recombinant IL-1Ra (anakinra) has been administered to over 1,000 patients with septic shock resulting in a consistent reduction in all-cause 28-day mortality. Approved for treatment of rheumatoid arthritis, anakinra has a remarkable safety record. Anakinra resulted in decreased blood vessels in the pannus of affected joints in patients with rheumatoid arthritis. Neutralizing monoclonal antibodies to IL-1β and a soluble receptor to IL-1 are approved for treating chronic inflammatory diseases. Given the availability of three therapeutic agents for limiting IL-1 activity, the safety of blocking IL-1, and the clear benefit of blocking IL-1 activity in animal models of metastasis and angiogenesis, clinical trials of IL-1 blockade should be initiated, particularly as an add-on therapy of patients receiving antiangiogenesis-based therapies.

Prostate cancer is the leading form of newly diagnosed cancer cases in men in the United States. However, the molecular mechanisms contributing to the initiation, progression and ultimate development of metastatic and androgen independent disease are poorly understood. This is due in part to the difficulty in obtaining clinical samples representing early disease and the lack of animal models that recapitulate the full spectrum of the clinical disease. To this end we have developed and characterized the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that expresses the oncogene SV40 T antigen specifically in the epithelium of the prostate. TRAMP develops spontaneous autochthonous prostate cancer compelte with distant site metastasis and can progress to androgen independent disease. Changes in the fibroblast growth factor (FGF) axis and the insulin-like growth factor (IGF) axis have been examined during prostate cancer progression utilizing the TRAMP model and these data generally support observations reproted in the clinical disease. Moreover, we report novel changes in the FGF axis and IGF axis utilizing TRAMP. Thus, TRAMP can be used as a potent tool in understanding the mechanism of prostate cancer initiation and progression.