Current Drug Targets - Volume 10, Issue 7, 2009

Our understanding of human cancers has been greatly enhanced by the study of developmental biology in model organisms. For example, the Nobel-prize winning genetic screens [1] that uncovered mutations impacting Drosophila developmental segmentation led to the discovery of many genes (such as Wingless/Wnt, Hedgehog, Patched, Armadillo/β-catenin) that were subsequently implicated in human cancers. As illustrated in the collection of articles published in this issue, studies of Drosophila development [2-6] continue to shape our understanding of human cancer. Furthermore, mouse models are enhancing the study of cancers in specific tissue types (i.e. breast, prostrate [7], and skin [8]) that are linked to genes of developmental importance. Work in these and other animal models combined with studies in human cancer cell lines are leading to the development of cancer therapies targeting genes of known developmental importance. Given that many of the hallmarks of human cancer, such as cell growth, invasion, evasion of apoptosis, and formation of a blood supply to the tumor, involve cellular processes that are critical during development, it is perhaps not surprising that scientific discoveries in developmental biology or cancer biology help to advance the alternate discipline. In fact, Gilbert [9] argues that there are many reasons to view cancer as a disease of development. He explains that the fates of cells during development and the malignancy of a tumor are dependent upon the cellular environment. This cellular environment is largely impacted by cell signaling, a critical aspect of both animal development and tumor malignancy. The functions of a number of developmental signaling molecules, including Rb/E2F [2], Myc [3], Netrins [4], Semaphorins [5], Wnts [6], FGFs [7], Integrins and TGFβs [8] in the contexts of both development and cancer biology are reviewed in this issue. Gilbert [9] points out that the study of stem cells and angiogenesis are excellent examples of research fields that encompass both developmental and cancer biology. The functions of Myc [3] and Wnt [6] in stem cell development are highlighted in this issue. Furthermore, the roles of Netrins [4], Semaphorins [5], and FGFs [7] in angiogenesis are examined. The process of invasive cell growth is another critical aspect of both developmental biology and metastastic cancer. The similarity between a developing neuron and a metastatic tumor cell, two cell types that undergo invasive migration, are discussed in this issue [4]. Invasive growth in both types of cells can be impacted by axon guidance molecules such as Netrin [4] and Semaphorin [5]. Given that very little is known about the genetic changes that result in metastastic cancer, analyzing the functions of axon guidance molecules and other developmental genes (see also FGFs [7] and Integrins [8] in this issue) in the regulation of invasive growth is critical. Such studies may provide clues regarding genetic changes that promote tumor cell metastasis, the leading cause of cancer-related deaths.

The retinoblastoma gene, Rb, was originally identified as the tumor suppressor gene mutated in a rare childhood cancer called retinoblastoma (reviewed in [1]). Subsequent studies showed that Rb functions in a pathway that is often functionally inactivated in a large majority of human cancers. Interestingly, recent studies showed that in certain types of cancers, Rb function is actually required for cancer development. The intimate link between the Rb pathway and cancer development suggests that the status of Rb activity can potentially be used to develop targeted therapy. However, a prerequisite will be to understand the role of Rb and its interaction with other signaling pathways in cancer development. In this review, we will discuss the roles of Rb in proliferation, apoptosis and differentiation by reviewing the recent findings in both mammalian systems and different model organisms. In addition, we will discuss strategies that can be employed that specifically target cancer cells based on the status of the Rb pathway.

The Myc family proteins are key regulators of animal growth and development. dMyc, the only Drosophila member of the Myc gene family, is orthologous to the mammalian c-Myc oncoprotein. Extensive studies have revealed much about both upstream regulators and downstream target genes in the sphere of Myc regulation. Here, we review some of the critical discoveries made using the Drosophila model, in particular those studies that have explored the essential role of the Myc family in growth and cell cycle progression and identified many of the upstream signals and downstream targets common to both c-Myc and dMyc.

In recent years, a number of axon guidance genes, including Netrin (Net) and Deleted in Colorectal Cancer (DCC), have been implicated in human cancers. Many of the hallmarks of human cancer, such as cell growth, invasion, evasion of apoptosis, and formation of a blood supply to the tumor, involve cellular processes that are critical during nervous system development. Here, the roles of Net-DCC in the regulation of these cellular processes in tumors and developing neurons are discussed. The advantages of using Drosophila to study the function of Net-DCC and other axon guidance molecules in these cellular processes, as well as the potential for cancer therapeutics targeting Net-DCC are highlighted.

Semaphorins (Semas), a family of evolutionarily conserved secreted and transmembrane proteins, were initially identified as axon guidance regulators and have since been implicated in the development of a number of other tissues. Sema signaling also regulates a variety of processes that are linked to cancer (i.e. metastasis, cell migration, cell growth). The mechanisms by which Sema signaling regulates axonogenesis and tumorigenesis are strikingly similar, making advances in either field applicable to the alternate discipline. Here, recent advances in understanding the roles of Semas in development and cancer, as well as the therapeutic potential for targeting this signaling pathway in human cancers, are reviewed.

The sequencing of whole genomes, including those of model organisms, has provided an unprecedented resource to the research community to make sense of the genetic code. However, it is the advent of novel functional genomic technologies that have been truly instrumental in bridging the gap between gene sequence and gene function. The past few years have witnessed a rapid growth in the development and implementation of high-throughput screening (HTS) technologies that researchers are now using to discover “gene-function” in an unbiased, systematic, time and costefficient manner. One of the most promising functional genomic approach that has emerged in the past few years is based on RNA-interference (RNAi) in which the introduction of double-stranded RNA (dsRNA) or short-interfering RNA (siRNA) into cells or whole organisms can effectively suppress endogenous gene expression. The RNAi-based screening technology has made it feasible to query the function of whole genomes in the regulation of conserved cell-signaling pathways and the crosstalk between them in “signaling networks” that are known to influence important cell biological functions, such as cell proliferation and growth, cell morphology, cell adhesion and cell death. In this review we discuss the application, advantages and limitations of RNAi and other post-genomic technologies in the identification of novel modulators of cell-signaling pathways, with a focus on the Wnt signaling pathway. We also discuss the future scope and utility of designing additional variants of these genome-scale screens.

The fibroblast growth factor (FGF) family is comprised of 22 ligands that bind and activate several FGF receptor (FGFR) isoforms. Critical roles for FGFs and FGFRs have been well-established during embryonic development. For example, the FGF10/FGFR2IIIb axis has been linked to embryonic development of both the mammary and prostate glands, which are the subject of this review. Furthermore, recent studies using novel mouse models have suggested that this pathway also participates in postnatal development in the mammary and prostate glands. These studies have provided novel insights into the mechanisms by which FGFs and FGFRs promote ductal outgrowth and branching morphogenesis. In addition to the established roles of FGFs in development, aberrant activation of the FGF pathway has been linked to tumor progression in both breast and prostate cancer. Recent studies have linked FGFR1 expression and single nucleotide polymorphisms in FGFR2 to breast cancer. Furthermore, novel pre-clinical models have demonstrated the ability of FGFRs to promote numerous aspects of breast and prostate cancer. Understanding the roles of FGFs in development will provide insights into the mechanisms by which deregulation of the FGF pathway leads to tumorigenesis, ultimately leading to the development of novel therapeutic strategies designed to target this pathway in cancer patients.

Integrins are a large family of heterodimeric transmembrane receptors that mediate cell-substratum adhesion. αvβ6 is an epithelial-specific integrin that is a receptor for the extracellular matrix (ECM) proteins fibronectin, vitronectin, tenascin and the latency associated peptide (LAP) of TGF-β. Integrin αvβ6 is not expressed in healthy adult epithelia but is upregulated during wound healing and in cancer. αvβ6 has been shown to modulate invasion, inhibit apoptosis, regulate the expression of matrix metalloproteases (MMPs) and activate TGF-β1. There is increasing evidence, primarily from in vitro studies, that suggest that αvβ6 may actually promote carcinoma progression. In this review we summarize what has been learnt in the past few years about the role of αvβ6 in cancer progression.

Although neurodegenerative diseases exhibit distinct pathologies, such as affected neuronal cell population, age of onset, and pathological symptoms, overlapping characteristics can be observed at the cellular level. In particular, several neurodegenerative diseases display defects in intracellular vesicular trafficking. Here we discuss the range of cellular phenotypes observed in two rare neurodegenerative diseases, Niemann-Pick Type C and Huntington's Disease, both of which involve vesicular trafficking defects that may contribute to neuronal cell death. In NPC, the primary defect is cholesterol and glycosphingolipid accumulation, but NPC mutant cells display widespread trafficking alterations. In HD, protein aggregates are a hallmark feature, but HD cells also exhibit changes in vesicular traffic, including axonal transport and early endosomal trafficking, that likely impact neuronal cell viability. Here we discuss current therapies that seek to address cellular defects in NPC and HD and describe areas of investigation that may lead to new therapeutic treatment.