Volume 10, Nº 2 (2010)

The idea that within the bulk of leukemic cells there are immature progenitors which are intrinsically resistant to chemotherapy and able to repopulate the tumor after treatment is not recent. Nevertheless, the term leukemia stem cells (LSCs) has been adopted recently to describe these immature progenitors based on the fact that they share the most relevant features of the normal hematopoetic stem cells (HSCs), i.e. the self-renewal potential and quiescent status. LSCs differ from their normal counterparts and from the more differentiated leukemic cells regarding the default status of pathways regulating apoptosis, cell cycle, telomere maintenance and transport pumps activity. In addition, unique features regarding the interaction of these cells with the microenvironment have been characterized. Therapeutic strategies targeting these unique features are at different stages of development but the reported results are promising. The aim of this review is, by taking acute myeloid leukemia (AML) as a bona fide example, to discuss some of the mechanisms used by the LSCs to survive and the strategies which could be used to eradicate these cells.

Despite recent advances in drug development, multiple myeloma (MM) remains incurable for the majority of patients due to relapse and disease progression. The cancer stem cell (CSC) hypothesis may provide an explanation for these clinical findings. It suggests that the long-term proliferative potential responsible for disease initiation, maintenance, and relapse is contained within specific subpopulations of biologically distinct tumor cells. Data in MM suggest that CSCs represent a rare cell population phenotypically resembling normal memory B cells. Compared to MM plasma cells, MM CSCs also appear to be relatively resistant to a wide variety of standard anti-cancer agents suggesting they may persist following treatment and mediate tumor re-growth and relapse. A unique property CSCs share with their normal counterparts is the potential for self-renewal that likely maintains the malignant clone over time. The development of therapeutic strategies targeting the signaling elements contributing to cancer cell self-renewal has been limited primarily because the cellular processes involved are poorly understood. However, it is common that the signaling pathway components regulating normal stem cell self-renewal are aberrantly activated in human cancers and may serve as potential therapeutic targets. One class of shared regulatory pathways are those active during normal embryonic patterning and organ formation such as Hedgehog (Hh), Notch and Wingless (Wnt), and emerging data suggest that these may play a role in CSCs. Here we review the identification and characterization of MM CSCs, the role of Hh in MM, and issues to be considered during the early clinical testing of CSC targeting agents.

Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.

Recent studies have suggested that a specific small population of cells termed tumor-initiating cells (TICs) may be intrinsically resistant to therapy including radiation, and may therefore be the primary mediators of recurrence. Numerous targets are being explored using multiple approaches for their involvement in the self-renewal or survival as well as radioresistance of breast TICs. These studies will provide a broad range of compounds to be tested and to develop novel TIC radiosensitizers that will improve clinical outcome and decrease recurrence of cancer after radiation. In this review we will discuss recent efforts to identify and target these cells to selectively radiosensitize them with novel agents, as well as the TIC radiosensitizing potential of current therapies already in clinical use.

Despite significant efforts in diagnosing and treating lung cancer, therapeutic resistance remains a major unresolved clinical and scientific problem. Cancer stem cells (CSCs) are thought to be responsible for the failure of current chemotherapy of lung cancer. The concept of CSCs has radically changed the view of cancer therapy. Today a majority of current treatment modalities target the differentiated cancer cells and avoid the drug resistant cancer-initiating stem cells. This review summarizes our understanding of lung CSCs and their role in metastasis formation and growth of non- small-cells lung cancer (NSCLC). High tumorigenic and metastatic properties of lung CSCs are associated with the efficient cytokine network production and with the specific signaling pathways. This review underlines the experimental evidence indicating that the stem cell factor (SCF) and its receptor c-kit (CD117) play an important role in survival and proliferation of lung CSCs. Thus, molecularly targeting key cytokine network axes of such highly tumorigenic and metastatic CSCs must be considered for improving the current anti-cancer strategy efficacy. Standard chemotherapy in combination with specific axis of cytokine network targeting, such as SCF-c-kit, could eliminate both bulk tumor cells and CSCs, and therefore to be truly curative therapies. This review provides a summary of some of the developments in the field of lung CSCs targeting and highlights aspects which could help in the drug discovery process.

Gestational trophoblastic neoplasia is a rare malignancy, which can occur after any type of pregnancy. The incidence varies according to the geographical location and ethnic origin. Although most patients with gestational trophoblastic neoplasia are cured by conventional chemotherapy and surgery, some suffer resistant disease and may die. New therapeutic agents are needed to reduce the toxicity associated with conventional chemotherapy and treat those with resistant or refractory disease. Molecular targeted treatment provides an exciting avenue; however, the biology of gestational trophoblastic neoplasia is not well understood. This review briefly summarises recent advances in the understanding of the pathogenesis and molecular biology of this group of diseases and sheds light on molecules that could provide potential therapeutic targets.