Mending and malignancy
Johns Hopkins University, Baltimore, Maryland, United States Nature
(Impact Factor: 41.46).
10/2004; 431(7007):402. DOI: 10.1038/431402a
Carcinogenesis and tissue repair: how might chronic tissue injury lead to the development of cancer?
Available from: Evgeny A Moskalev
- "The biological starting point of carcinogenesis could be an aberrant launch of developmental or regenerative programmes in stem cells (Beachy et al., 2004; Widschwendter et al., 2007). The facts that epigenetic programming is involved in cell fate specification (Brö ske et al., 2009) and that ubiquitous and concurrent epigenetic alterations are detectable already during very early stages of tumor development (Crawford et al., 2004; Issa, 2004; Suzuki et al., 2004) strongly suggest that epigenetic disruption in stem cells may be a unifying theme in cancer etiology (Feinberg et al., 2006). "
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ABSTRACT: Epigenetic aberrations are recognized as an early and common event during carcinogenesis. This provides a strong rationale for a therapeutic intervention at the epigenetic level. Current epigenetically active drugs, however, lack specificity for particular genomic loci. Better processes for a more targeted manipulation of the cancer epigenome are needed. One option could be the ability of long noncoding RNAs (lncRNAs) to recruit the chromatin modification complexes to particular genomic loci. In consequence, epigenetic variations would not be stochastic but controlled by a directed programme, through which specific groups of genes are regulated by promoter methylation and(or) histone marks, even if located on different chromosomes. lncRNAs are known to be functionally involved in cell fate specification and carcinogenesis. Depleting lncRNAs with oncogenic potential or replacing scarce molecules with tumor suppressor activity could therefore be employed for a specific reprogramming of the epigenome of cancer cells. Apart from the targeted manner and thus specificity, the mode of action by itself could be an advantage of lncRNA-associated therapy. Similar to what happens naturally during cell fate decisions, the whole developmental programme of a cell or particular parts of it could be reset. In consideration of the early onset of epigenetic aberrations, such an approach could even be useful for cancer prevention.
Available from: PubMed Central
- "It is well established that there is a relationship between tissue repair and cancer, implying that chronic tissue injury may lead to malignancy (see e.g. ). A well-known example is colon cancer developing in longstanding ulcerative colitis. "
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ABSTRACT: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice.
Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal (3)H-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves.
Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or (3)H-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments.
Enteric nerves are of importance in maintaining the intestinal epithelial barrier.
Available from: Gil Mor
- "tail vein injection of 4T1 mouse mammary carcinoma cells showed an increase in lung metastases following LPS injection (Harmey et al., 2002). In humans, chronic infection and inflammation are considered two of the most important epigenetic and environmental factors contributing to tumorigenesis and tumor progression (Balkwill and Coussens, 2004; Beachy et al., 2004). "
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ABSTRACT: Cancer could be deemed as an abnormal and uncontrolled tissue repair process. Therefore, it would not be surprising that factors that function in the tissue repair process, such as cytokines, chemokines, growth factors and Toll-like receptor (TLR) ligands, as well as growth signals for compensatory proliferation, would also be key factors in regulating and enhancing cancer progression. The TLR pathways, which play a critical role in tissue repair, are also key regulators in cancer progression as well as chemoresistance. TLRs serve as cell surface sensors that can initiate pathways leading to proliferation and chemoresistance; as well as mediators that are able to regulate the infiltrating immune cells to provide further support for cancer progression.
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