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Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies [ABSTRACT FROM AUTHOR]

An abstract of the medical research article "Targeting Non-Viral Vectors to Tumor Cells and the Tumor Microenvironment," that was presented at the 16th International Charles Heidelberger Symposium on Cancer Research held in Portugal in September 2010, is presented.

Abstract: The present work aimed at designing a lipid-based nanocarrier for siRNA delivery toward two cell sub-populations within breast tumors, the cancer and the endothelial cells from angiogenic tumor blood vessels. To achieve such goal, the F3 peptide, which is specifically internalized by nucleolin overexpressed on both those sub-populations, was used as a targeting moiety. The developed F3-targeted stable nucleic acid lipid particles presented adequate features for systemic administration. In addition, the attachment of the F3 peptide onto the liposomal surface enabled an internalization by both cancer and endothelial cells from angiogenic blood vessels that was significantly higher than the one observed with non-cancer cells. Sequence-specific downregulation of enhanced green fluorescent protein (eGFP) in eGFP-overexpressing human cancer cell lines, both at the protein and mRNA levels, was further observed upon delivery of anti-eGFP siRNA by F3-targeted liposomes, in contrast with the non-targeted counterpart. This effect was highly dependent on the content of poly(ethylene glycol) (PEG), as evidenced by the co-localization studies between the siRNA and the lysosomes. Overall, the present work represents an important contribution toward a nanoparticle with multi-targeting capabilities in breast cancer, both at the cellular and molecular level. [Copyright &y& Elsevier]

Acute Lymphoblastic Leukemia (ALL) is the most prevalent type of cancer, as well as the most common form of leukemia in children. In general, contemporary treatment protocols achieve overall long- term survival rates of 70% to 80%. Nevertheless, patients with T-cell lineage ALL (T-ALL), an aggressive form of the disease, require intensive chemotherapy regimens and often remain refractory to treatment. Therefore, it has already been recognized that alternative therapies are urgently needed for this sub-group of patients.Antisense oligonucleotides (asODNs) have been considered promising tools for the treatment of a variety of malignant diseases due to their ability to specifically inhibit gene expression. However, the successful application of antisense therapy, strongly relies on the development of formulations capable of protecting the genetic material from premature degradation, promoting its specific delivery to target cells or tissues and enhancing its intracellular delivery.In this study, we investigated the efficacy of novel liposome-based strategies to inhibit leukemia cell proliferation in vitro. Formulations consisted of sterically stabilized pH-sensitive liposomes bearing coupled transferrin (Trf) and encapsulating asODNs against mRNA of dihidrofolate reductase (DHFR). In addition, an appropriate animal model of human T-ALL was developed using severe combined immune deficient (SCID) mice and used to evaluate the in vivo anti-tumoral activity mediated by the developed formulations.Significant levels of cytotoxicity were observed upon treatment of HSB-2 cells with targeted liposomes encapsulating asODNs as compared to free drug or a control formulation. Accordingly, a significant reduction on the levels of mRNA and of DHFR activity was observed. Human HSB-2 leukemia cells were successfully engrafted into SCID mice and disseminated in a pattern analogous to human disease, with the presence of malignant cells in blood, bone marrow and infiltration of peripheral organs. Animals treated with asODNs encapsulated in targeted liposomes had significantly less percentage of tumor cells at the sites most frequently manifesting leukemic cell infiltration (such as bone marrow and spleen) as compared to animals treated with free asODNs.Overall, these formulations can be considered promising delivery systems for in vivo targeting of asODNs to leukemia cells and may constitute a novel strategy for the treatment of human leukemias.Molecular Therapy (2006) 13, S372–S372; doi: 10.1016/j.ymthe.2006.08.1059 [ABSTRACT FROM AUTHOR]

Abstract: Anticancer systemic gene silencing therapy has been so far limited by the inexistence of adequate carrier systems that ultimately provide an efficient intracellular delivery into target tumor cells. In this respect, one promising strategy involves the covalent attachment of internalizing-targeting ligands at the extremity of PEG chains grafted onto liposomes. Therefore, the present work aims at designing targeted liposomes containing nucleic acids, with small size, high encapsulation efficiency and able to be actively internalized by SCLC cells, using a hexapeptide (antagonist G) as a targeting ligand. For this purpose, the effect of the liposomal preparation method, loading material (ODN versus siRNA) and peptide-coupling procedure (direct coupling versus post-insertion) on each of the above-mentioned parameters was assessed. Post-insertion of DSPE-PEG-antagonist G conjugates into preformed liposomes herein named as stabilized lipid particles, resulted in targeted vesicles with a mean size of about 130 nm, encapsulation efficiency close to 100%, and a loading capacity of approximately 5 nmol siRNA/μmol of total lipid. In addition, the developed targeted vesicles showed increased internalization in SCLC cells, as well as in other tumor cells and HMEC-1 microvascular endothelial cells. The improved cellular association, however, did not correlate with enhanced downregulation of the target protein (Bcl-2) in SCLC cells. These results indicate that additional improvements need to be performed in the future, namely by ameliorating the access of the nucleic acids to the cytoplasm of the tumor cells following receptor-mediated endocytosis. [Copyright &y& Elsevier]