Cardiac function is determined by the coordinated and dynamic interaction of several cell types together with components of the extracellular matrix (ECM). This interaction is regulated by mechanical, chemical, and electrical signals between the cellular and noncellular components of the heart. Recent studies using fluorescence-activated cell sorting indicate that the number of myocytes remains relatively constant during development and disease, whereas the number of fibroblasts and other cell types can change dramatically. Cardiac fibroblasts appear to have different origins at different stages of development and fluctuate in response to a variety of physiological signals. Fibroblasts form a network of cells that are connected to each other via specific cadherins and connexins, to the ECM via integrins, and to myocytes by a variety of receptors, including connexins. Examples of the integration of signals include the role of angiotensin II (Ang II), which stimulates mechanical contraction of fibroblasts, as well as cytokine signaling. Cytokine signaling alters connexin and K(+) channel activation, which in turn is regulated by Ang II, essentially forming a feedback loop. Quantitative changes in mechanical, chemical, and electrical signals that can alter the overall cardiac form and function will be discussed here.

The c-myc oncogene plays an important role in tumorigenesis and is frequently deregulated in many human cancers, including gastrointestinal cancers. In humans, mutations of the adenomatous polyposis coli (Apc) tumor suppressor gene occur in most colorectal cancers. Mutation of Apc leads to stabilization of B-catenin and increases in B-catenin target gene expression (c-myc and cyclin D1), whose precise functional significance has not been examined using genetic approaches. Apc Min/+ mice are a model of familial adenomatous polyposis and are heterozygous for an Apc truncation mutation. We have developed a model for examining the role of c-Myc in Apc-mediated tumorigenesis. We crossed c-myc +/À mice to Apc Min/+ to generate Apc Min/+ c-myc +/À animals. The compound Apc Min/+ c-myc +/À mice were used to evaluate the effect of c-myc haploinsufficiency on the Apc Min/+ phenotype. We observed a significant reduction in tumor numbers in the small intestine of Apc Min/+ c-myc +/À mice compared with control Apc Min/+ c-myc +/+ mice. In addition, we observed one to three polyps per colon in Apc Min/+ c-myc +/+ mice, whereas only two lesions were observed in the colons of Apc Min/+ mice that were haploinsufficient for c-myc. Moreover, reduction in c-myc levels resulted in a significant increase in the survival of these animals. Finally, we observed marked decreases in vascular endothelial growth factor, EphA2, and ephrin-B2 expression as well as marked decreases in angiogenesis in intestinal polyps in Apc Min/+ c-myc +/À mice. This study shows that c-Myc is critical for Apc-dependent intestinal tumorigenesis in mice and provides a potential therapeutic target in the treatment of colorectal cancer. (Mol Cancer Res 2007;5(12):1296 -303)

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Tumors are supported by the development of a unique vascular bed. We used fractal dimension (Db) and image analysis to quantify differences in the complexity of the vasculature in normal intestinal submucosa and intestinal polyps. Apc(Min/+) mice and wild-type mice were perfused with a curable latex compound, intestines sectioned, and images collected via confocal microscopy. The images were analyzed and area (A), perimeter (P), and integrated optical density (IOD) of the normal and tumor vascular beds were measured. The Db, a quantitative descriptor of morphological complexity, was significantly greater for the polyp vasculature from Apc(Min/+) mice than controls. This indicates that the polyp microvasculature is more chaotic than that of the controls, while the IOD and average vascular density values displayed no differences. This suggests the mass of blood volume is equivalent in normal and polyp microvasculature. The lower vascular area-perimeter ratios expressed by the polyp microvasculature suggest it is composed of smaller, more tortuous vessels. These data demonstrate that fractal analysis is applicable for providing a quantitative description of vascular complexity associated with angiogenesis occurring in normal or diseased tissue. Application of Db, IOD, and average density provides a clearer quantification of the complex morphology associated with tissue microvasculature.