p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance.

Chemoresistance persists as a significant, unresolved clinical challenge in many cancer types. The tumor microenvironment, in which cancer cells reside and interact with non-cancer cells and tissue structures, has a known role in promoting every aspect of tumor progression, including chemoresistance. However, the molecular determinants of microenvironment-driven chemoresistance are mainly unknown. In this review, we propose that the TP53 tumor suppressor, found mutant in over half of human cancers, is a crucial regulator of cancer cell-microenvironment crosstalk and a prime candidate for the investigation of microenvironment-specific modulators of chemoresistance. Wild-type p53 controls the secretion of factors that inhibit the tumor microenvironment, whereas altered secretion or mutant p53 interfere with p53 function to promote chemoresistance. We highlight resistance mechanisms promoted by mutant p53 and enforced by the microenvironment, such as extracellular matrix remodeling and adaptation to hypoxia. Alterations of wild-type p53 extracellular function may create a cascade of spatial amplification loops in the tumor tissue that can influence cellular behavior far from the initial oncogenic mutation. We discuss the concept of chemoresistance as a multicellular/tissue-level process rather than intrinsically cellular. Targeting p53-dependent crosstalk mechanisms between cancer cells and components of the tumor environment might disrupt the waves of chemoresistance that spread across the tumor tissue, increasing the efficacy of chemotherapeutic agents.

3-D Endoluminal Ultrasound Biomicroscopic Imaging and Volumetry of Mouse Colon Tumors.

Currently, colonoscopy is considered the gold standard procedure for diagnosis of colorectal cancer (CRC), the third most common cancer in the United States. However, this technique fails to detect flat adenomas, serrated polyps and advanced adenomas, with miss rates of 34%, 27% and 14%, respectively. These miss rates, more frequent than previously supposed, suggest the need for new CRC screening tools. In the work described here, the potential application of a 40-MHz ultrasound system to generate a sequence of 2-D endoluminal ultrasound biomicroscopy (eUBM-2-D) images of a mouse model of colon cancer was investigated, and this image sequence was used to render eUBM-3-D images and to measure tumor volume. The technique was validated with tissue-mimicking phantoms and used in vivo with mice bearing colon polypoid tumors. Estimated volumes ranged from 0.174-7.909 mm3 for targets in validation phantoms and from 0.066-6.082 mm3 for mouse colon tumors.

The Chalcone Lonchocarpin Inhibits Wnt/ß-Catenin Signaling and Suppresses Colorectal Cancer Proliferation.

The deregulation of the Wnt/ß-catenin signaling pathway is a central event in colorectal cancer progression, thus a promising target for drug development. Many natural compounds, such as flavonoids, have been described as Wnt/ß-catenin inhibitors and consequently modulate important biological processes like inflammation, redox balance, cancer promotion and progress, as well as cancer cell death. In this context, we identified the chalcone lonchocarpin isolated from Lonchocarpus sericeus as a Wnt/ß-catenin pathway inhibitor, both in vitro and in vivo. Lonchocarpin impairs ß-catenin nuclear localization and also inhibits the constitutively active form of TCF4, dnTCF4-VP16. Xenopus laevis embryology assays suggest that lonchocarpin acts at the transcriptional level. Additionally, we described lonchocarpin inhibitory effects on cell migration and cell proliferation on HCT116, SW480, and DLD-1 colorectal cancer cell lines, without any detectable effects on the non-tumoral intestinal cell line IEC-6. Moreover, lonchocarpin reduces tumor proliferation on the colorectal cancer AOM/DSS mice model. Taken together, our results support lonchocarpin as a novel Wnt/ß-catenin inhibitor compound that impairs colorectal cancer cell growth in vitro and in vivo.