Progress in Tumor Research最新文献

Other sections of this monograph, dedicated to neuronal activities in tumor tissue, have highlight the chief influence of neurotrophins, neurotransmitters, adhesion, guidance molecules and different nerve cell markers in the progression, but also for the prognostic, therapy and survey of cancers. The G-protein-coupled receptors (GPCR) are among the most successful and promising target proteins for drug discovery and therapeutic research. GPCR are frequently overexpressed in cancer cells, an interesting property for tumor imaging or for a targeted radiotherapy, using radiolabeled ligand derivatives. The tumor microenvironment contains a number of GPCR ligands (e.g., bioactive peptides, biogenic amines, purins, chemokines), known to regulate the proliferation, migration or survival of both tumoral and neural cells and that may be key actors of the neuro-neoplastic interactions. Here will be reviewed the potential utilization of substances that target a selected choice of GPCR, especially neuropeptide receptors, for a novel concept of therapy, concerning the numerous types of cancers where neurons infiltrate the tumoral mass or those where the malignant cells invade nerve branches (perineural invasion). Some molecular mechanisms linked to these GPCR (or linking GPCR to other types of membrane receptors or co-receptors), involved in these processes, will also be considered.

Since the pioneering work of Judah Folkman and colleagues in the 1970s on tumor neoangiogenesis, we learned more and more about the heterogeneity of the cellular, subcellular and stromal architecture within a tumor mass. The research on neoangiogenesis has lead to novel molecular entities (vascular endothelial growth factor, platelet-derived growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, transforming growth factor-Beta, tumor necrosis factor-alpha, interleukin-8), which can be targeted within the framework of tumor neoangiogenesis inhibition. Accepting the paradigm of anti-angiogenic therapy, a new class of drugs could be developed some of which already obtained clinical approval. As blood vessels and nerves often follow parallel trajectories within a tumor tissue, it was consequent to argue that tumor cells for their growth advantage and survival and metastases formation use common cues that induce vascularization and innervation. Autocrine, paracrine or endocrine interactions between a resident tumor cell type with neurocrine cell types and their signaling molecules can be regarded as a neuro-neoplastic synapse. That cross-talk molecules are equally interesting molecules as selectable anti-tumor targets as it turned out to be in the past for tumor angiogenesis factors. An extended model of human tumor dormancy as well as metastasis formation is provided assuming an angiogenic and neurogenic switch from the non-angiogenic and non-neurogenic phenotype.

Many proteins first identified in the nervous system were also found to be expressed elsewhere in the body. The text reviews some of these 'neuronal' markers and delineates intersections between nervous and non-nervous tissues on the structural and functional level. Examples are given for nuclear antigens, cytosolic, cytoskeletal and membrane bound proteins, neurotrophic factors and developmental antigens. Clinical aspects of the expression of neuronal antigens in cancer-like paraneoplastic syndromes of the nervous system and tumor invasion along and within peripheral nerves are discussed. The accumulated data indicates that expression of "neuronal" protein in tumors may promote proliferation, invasiveness and metastatic spread. The large spectrum of neuronal antigens expressed in cancer including voltage-gated ion channels and numerous neurotrophic factors reflects the continuity from neuronal to non-neuronal differentiation.

During the last 10 years new evidence has come to light which shows that the biology of neurotransmitters has expanded beyond their traditional role as chemical messengers, which is the release from a neuron, diffusion across a synaptic cleft, binding to and stimulation of a post-synaptic cell. These external signaling substances of the nervous system have been found to exert a strong influence on cells of the immune system and tumor cells. The latter express neurotransmitter receptors and several studies demonstrate the involvement of neurotransmitters in tumor cell progression and metastasis development. Besides their impact on the migration of lymphocytes, which is of primary importance for an anti-tumor response, neurotransmitters comprise a multitude of other immunomodulatory properties, which differ depending on the cell type and cell function. To illuminate the interplay between the nervous system, the immune system and tumor cells, we herein summarize in vitro and in vivo experiments on the effects of neurotransmitters on the migratory activity, proliferation and survival of tumor cells, as well as on the function of leukocytes.

Bone-marrow-derived and tissue-resident stem cells promote repair of injured tissues by contributing to new blood vessel, muscle and nerve formation. These same stem cells may contribute to tumor growth and spread. Tumors express numerous growth factors that induce both angiogenesis and neurogenesis; these factors may also induce tissue-resident stem cell recruitment and differentiation. Tumors also recruit circulating bone-marrow-derived stem or progenitor cells, which play roles in promoting tumor growth and spread. As innervation of tumors promote cancer pain and can contribute to tumor spread, an understanding of the roles of stem cells in tumor innervation will assist in the development of new cancer therapies.

Biological tools that are unleashed in malignancies are employed in a controlled manner during neuronal development. By default, early embryonic cells would become neuronal stem cells, a path that is blocked by specific signaling pathways. The future nervous system only develops where this blockade is inhibited by inductive signals from the 'organizer'. Once the future brain and spinal cord regions are determined, the mitotic potential in this region must be maintained long enough to produce all cells required, but also be controlled to avoid excessive over-production of cells. Newly generated cells must then migrate to their future destination, they must know where to settle down, and they must differentiate. To shape the developing nervous system and to adapt its functionality to the postnatal environment, cell survival must be regulated, i.e. survival of some cells is supported while death of others is induced. Thus, inductive events, proliferation, cell migration, differentiation, cell survival and cell death are highly regulated during neuronal development, while these functions are de-regulated in malignancies. The molecular pathways for neuronal development mutually modulate each other and are still present in the adult nervous system. Because many of these pathways are implicated in tumors, neurons may affect these conditions.

A tumor is not an isolated entity within an organism, but tissue that strongly interacts with its environment. This interaction is however not restricted to direct cell-to-cell interactions, but generally comprises the susceptibility of tumor cells for chemokines and cytokines, as well as neurotransmitters and hormones by the expression of the according receptors. These signal substances have influences on tumor cell functions such as proliferation and migration. The other way round, tumor cells themselves release a broad range of these signal substances, which influence the cells of the environment. One of the first and most important interactions in this respect is the angiogenesis, which was discovered about 30 years ago. Tumor cells release angiogenic factors, i.e. the vascular endothelial growth factor as well as angiogenic chemokines among others. These factors initiate the vascularization of the tumor. Recently, a similar process was found for the development of lymphatic vessels in tumors. We herein seize these observations and combine them with arguments provided in the previous chapter, which leads us to the hypothesis that tumor cells may also be able to stimulate their own innervation; a process that we have termed neoneurogenesis.