ABSTRACT
Neuroblastoma (NBL), the most frequent and lethal pediatric cancer of children in pre-school age, is considered enigmatic in view of its extreme heterogeneity, from spontaneous regression in the IV-S form to incurable disease in approx. 40% of cases (High Risk, HR-NBL). It has an embryonal origin and a very heterogeneous genomic landscape, hampering the success of targeted strategies. The glycosphingolipid GD2 was shown to be expressed on NBL cells and utilized as target for passive immunotherapy with anti-GD2 antibodies (GD2-IMT). An international protocol was established with GD2-IMT, which increases remission length and survival in HR-NBL. By reviewing the different biological and molecular aspects of NBL and GD2-IMT, this mini-review questions the present lack of association between GD2-IMT and the underlying molecular landscape. The alternative model of Micro-Foci inducing virus (MFV) is presented, since MFV infection can induce extensive genomic aberrations (100X NMYC DNA-amplification). Since this family of viruses uses molecules for cell penetration similar to GD2 (i.e., GM2), it is hypothesized that GD2 is the port-of-entry for MFV and that success of anti-GD2 therapies is also associated to inhibition of this clastogenic virus in HR-NBL.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Gangliosides/metabolism , Neuroblastoma/drug therapy , Antineoplastic Agents, Immunological/immunology , Child, Preschool , Clinical Trials as Topic , Gangliosides/immunology , Genetic Heterogeneity , Humans , Immunization, Passive , Neuroblastoma/genetics , Neuroblastoma/metabolismABSTRACT
It is today indisputable that great progresses have been made in our molecular understanding of cancer cells, but an effective implementation of such knowledge into dramatic cancer-cures is still belated and yet desperately needed. This review gives a snapshot at where we stand today in this search for cancer understanding and definitive treatments, how far we have progressed and what are the major obstacles we will have to overcome both technologically and for disease modelling. In the first part, promising 3rd/4th Generation Sequencing Technologies will be summarized (particularly IonTorrent and OxfordNanopore technologies). Cancer modelling will be then reviewed from its origin in XIX Century Germany to today's NGS applications for cancer understanding and therapeutic interventions. Developments after Molecular Biology revolution (1953) are discussed as successions of three phases. The first, PH1, labelled "Clonal Outgrowth" (from 1960s to mid 1980s) was characterized by discoveries in cytogenetics (Nowell, Rowley) and viral oncology (Dulbecco, Bishop, Varmus), which demonstrated clonality. Treatments were consequently dominated by a "cytotoxic eradication" strategy with chemotherapeutic agents. In PH2, (from the mid 1980s to our days) the description of cancer as "Gene Networks" led to targeted-gene-therapies (TGTs). TGTs are the focus of Section 3: in view of their apparent failing (Ephemeral Therapies), alternative strategies will be discussed in review part II (particularly cancer immunotherapy, CIT). Additional Pitfalls impinge on the concepts of tumour heterogeneity (inter/intra; ITH). The described pitfalls set the basis for a new phase, PH3, which is called "NGS Era" and will be also discussed with ten emerging cancer models in the Review 2nd part.
Subject(s)
High-Throughput Screening Assays/history , High-Throughput Screening Assays/methods , Neoplasms/history , History, 20th Century , History, 21st Century , HumansSubject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Megakaryocyte Progenitor Cells/pathology , Platelet Aggregation Inhibitors/therapeutic use , Quinazolines/therapeutic use , Thrombocythemia, Essential/complications , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathologySubject(s)
Cell Transformation, Neoplastic , Mycosis Fungoides/etiology , Skin Neoplasms/etiology , T-Lymphocytopenia, Idiopathic CD4-Positive/pathology , Aged , Disease Progression , Humans , Lymphocytes, Tumor-Infiltrating/pathology , Male , Mycosis Fungoides/diagnosis , Skin/pathology , Skin Neoplasms/diagnosis , T-Lymphocytopenia, Idiopathic CD4-Positive/diagnosisABSTRACT
In July 2010, at the Muscle Fatigue Meeting, I presented an overview of Chronic Fatigue Syndrome and Cancer Related Fatigue, emphasizing a critical interpretation of the potential association between Chronic Fatigue Syndrome and Cancer Related Fatigue and a newly discovered retrovirus: Xenotropic Murine Related Virus. Since this association was hotly debated at that time, I suggested at the Meeting that it was wrong and most likely due to the identification of the wrong virus culprit. Today, 20 months after the Meeting, the first part of our prediction has turned out to be correct, as Xenotropic Murine Related Virus was shown to be a laboratory-created artefact. Still, the potential association of fatigue-syndromes with an infection (most likely viral) is sustained by a plethora of evidence and this overview will initially summarize data suggesting prior viral infection(s). The principal hypothesized mechanisms for both peripheral and central Chronic Fatigue Syndrome/Cancer Related Fatigue will be then summarized, also indicating plausible associations and triggering factors. All evidence accrued so far suggests that further research work should be performed in this interesting area and in order to identify an infectious agent for Chronic Fatigue Syndrome/Cancer Related Fatigue. One candidate RNA virus, Micro-Foci inducing Virus, will be described in this overview.
