Anti-Cancer Agents in Medicinal Chemistry - Volume 10, Issue 2, 2010

New concepts on carcinogenesis process suggest that the malignant transformation of adult stem/progenitor cells and/or their progenies endowed with stem cell-like properties into highly leukemic or tumorigenic cancer stem/progenitor cells may provide critical functions in cancer initiation and progression to locally invasive and metastatic cancers, treatment resistance and disease relapse [1, 2]. In support with this hypothesis, the cancer stem/progenitor cells, also designated as cancer-, leukemia-, tumor- or metastasis-initiating cells endowed with stem cell-like properties have been identified and isolated from a variety of human primary and metastatic cancers and established cancer cell lines [1, 2]. It has been shown that these immature cancer cells with high self-renewal potential and aberrant differentiation ability were able to giving rise to the total cancer cell mass that recapitalized the histological and cytological architecture of original patient's leukemias or tumors [1, 2]. In addition, numerous accumulating lines of experimental evidence have also revealed that the resistance of cancer stem/progenitor cells to current anti-hormonal, radiation and chemotherapeutic treatments may lead to their persistence at the primary cancers and metastatic sites after therapy initiation and disease recurrence [1, 2]. Therefore, the development of novel targeted approaches to eradicating the total cancer cell mass, including highly leukemic or tumorigenic cancer stem/progenitor cells and their progenies, is of immense clinical interest for improving current cancer treatments. These novel combination therapies should be effective to treat the patients diagnosed with advanced cancers, and thereby prevent disease relapse and the death of cancer patients [2]. In this special issue, the experimented researchers specialized on different aspects related to carcinogenesis process and drug development research will review for us the most recent advancements on the identification of immature cancer cells with the stem cell-like properties in different aggressive and recurrent cancer types. The therapeutic implications of these recent progresses for the development of novel effective cancer therapies will also be discussed. More specifically, novel potential therapeutic drug targets in cancer- and metastasis-initiating cells and their progenies and important foundings in the development of novel pharmacological agents for eradicating the cancer stem/progenitor cells and improving the current clinical cancer treatments will be reviewed. The subtopics covering in this special issue include leukemia-initiating cells (acute myeloid leukemia “AML” and chronic myeloid leukemia “CML”) as well as diverse tumor- and metastasis-initiating cells involved in multiple myeloma, brain and melanoma and diverse epithelial tumors such as prostate, pancreas, breast, ovarian, lung and liver cancers. Especially, the emphasis is on the critical functions of these immature cells in cancer initiation and progression, metastases at distant tissues, treatment resistance and disease relapse. Of therapeutic interest, potential therapeutic drug targets in cancer-initiating cells and novel targeted therapies and combination cancer therapies will be reviewed. Moreover, the importance to also consider the molecular targeting of host tumor microenvironment of cancer stem/progenitor cells is also discussed. Other promising therapeutic approaches to treat cancer patients discussed in this special issue also include novel stem cellbased cancer therapies, selective delivery strategies of anti-cancer drugs (nanoparticule- and liposome-based systems), anti-angiogenic treatments and immunotherapies. Taken together, information provided in this special issue should help researchers to develop novel combination therapies by molecular targeting of both highly tumorigenic cancer stem/progenitor cells and their progenies for a most effective treatment of cancer patients diagnosed at early and late stages with aggressive, metastatic and lethal cancers.

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.

Chronic myeloid leukemia (CML) is induced by the BCR-ABL oncogene, a product of Philadelphia (Ph) chromosome. The BCR-ABL kinase inhibitor imatinib is a standard treatment for Ph+ leukemia, and has been shown to induce a complete hematologic and cytogenetic response in most chronic phrase CML patients. However, imatinib does not cure CML, and one of the reasons is that imatinib does not kill leukemia stem cells (LSCs) in CML both in vitro and in vivo. Recently, several new targets or drugs have been reported to inhibit LSCs in cultured human CD34+ CML cells or in mouse model of BCR-ABL induced CML, including an Alox5 pathway inhibitor, Hsp90 inhibitors, omacetaxine, hedgehog inhibitor and BMS-214662. Specific targeting of LSCs but not normal stem cell is a correct strategy for developing new anti-cancer therapies in the future.

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.

The role of neural stem cells (NSCs) in both the physiological and pathological processes in the brain has been refined through recent studies within the neuro-oncological field. Alterations in NSC regulatory mechanisms may be fundamental for the development and progression of malignant gliomas. A subpopulation of cells within the tumor known as brain tumor stem cells (BTSCs) have been shown to share key properties with NSCs. The BTSC hypothesis has significantly contributed to a potential understanding as to why brain tumors hold such dismal prognosis. On the other hand, the normal NSCs possess the capacity to migrate extensively towards the tumor bulk as well as to lingering neoplastic regions of the brain. The tropism of NSCs towards brain tumors may provide an additional tool for the treatment of brain cancer. The creation of potential therapies through the use of NSCs has been studied and includes the delivery of gene products to specific locations of the central nervous system selectively targeting malignant brain tumor cells and maximizing the efficiency of their delivery. Here, the proposed mechanisms of how brain tumors emerge, the molecular pathways interrupted in NSC pathogenesis and the most recent preclinical results in the use of NSCs for glioma treatment are reviewed.

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.

A growing body of experimental evidence has revealed that the highly tumorigenic cancer stem/progenitor cells endowed with stem cell-like properties might be responsible for initiation and progression of numerous aggressive epithelial cancers into locally invasive, metastatic and incurable disease states. The malignant transformation of tissue-resident adult stem/progenitor cells or their progenies into tumorigenic and migrating cancer stem/progenitor cells and their resistance to current cancer therapies have been associated with their high expression levels of specific oncogenic products and drug resistance-associated molecules. In this regard, we describe the tumorigenic cascades that are frequently activated in cancer stem/progenitor cells versus their differentiated progenies during the early and late stages of the epithelial cancer progression. The emphasis is on the growth factor signaling pathways involved in the malignant behavior of prostate and pancreatic cancer stem/progenitor cells and their progenies. Of clinical interest, the potential molecular therapeutic targets to eradicate the tumor- and metastasis-initiating cells and their progenies and develop new effective combination therapies against locally advanced and metastatic epithelial cancers are also described.

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.

Evidence supports that a variety of cancers are sparked by the growth of cells that exhibit characteristics of stem cells. Such cancer-initiating cells are capable of populating a tumor with a heterogeneous group of daughter cells while still maintaining the ability to self-renew. Several groups have recently reported the identification of cancer-initiating cells in ovarian cancer, the most lethal gynecologic malignancy. Epithelial ovarian cancer comprises 90% of cancers of the ovary and consists of four major histologic types, each bearing some resemblance to different tissues in the peritoneal cavity. Although epithelial ovarian cancer has traditionally been thought to originate from the single layer of cells surrounding each ovary, new findings suggest that many of these cancers derive from Mullerian epithelium. This raises questions about the origin of ovarian cancer-initiating cells, and if there may be more than one source. Despite the initial effectiveness of primary therapy against advanced stage ovarian cancer, most of these cases recur, months to years following diagnosis. The cause of disease recurrence is unknown, but may involve cancer-initiating cells that survive chemotherapy and enter a period of dormancy while residing in as-yet undefined niches within the body before being triggered to initiate renewed growth. Herein the nature of these cells is explored as well as novel approaches for therapeutic targeting.

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.

Hepatic cancer is one of most common cause of cancer-related death. Hepato-epithelial cancers are believed to originate from the malignant transformation of liver-resident stem/progenitor cells. Liver cancer stem cells have been characterized recently and the phenotype of liver cancer stem cells has been defined as CD133+ CD44+ cancer cells. Recently, it has been also demonstrated about the relevance of targeting liver cancer stem cells, due to cancer stem cells are related to cancer metastasis. These advances no doubt to bring the new strategy in liver cancer treatment and control in this disease. This review describes the current status and progress about cancer stem cell research in liver and discuss of the implications of these studies in new liver cancer treatment strategies.

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.