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S100A4, a calcium-binding protein, is known for its role in the metastatic spread of tumor cells, a late event of cancer disease. This is the first report showing that S100A4 is not merely a metastatic protein but also an oncoprotein that plays a critical role in the development of tumors. We earlier showed that S100A4 expression progressively increases in prostatic tissues with the advancement of prostate cancer (CaP) in TRAMP, an autochthonous mouse model. To study the functional significance of S100A4 in CaP, we generated a heterozygously deleted S100A4 (TRAMP/S100A4(+/-)) genotype by crossing TRAMP with S100A4(-/-) mice. TRAMP/S100A4(+/-) did not show a lethal phenotype, and transgenes were functional. As compared to age-matched TRAMP littermates, TRAMP/S100A4(+/-) mice exhibited 1) an increased tumor latency period (P < 0.001), 2) a 0% incidence of metastasis, and 3) reduced prostatic weights (P < 0.001). We generated S100A4-positive clones from S100A4-negative CaP cells and tested their potential. S100A4-positive tumors grew at a faster rate than S100A4-negative tumors in vitro and in a xenograft mouse model. The S100A4 protein exhibited growth factor-like properties in multimode (intracellular and extracellular) forms. We observed that 1) the growth-promoting effect of S100A4 is due to its activation of NFκB, 2) S100A4-deficient tumors exhibit reduced NFκB activity, 3) S100A4 regulates NFκB through the RAGE receptor, and 4) S100A4 and RAGE co-localize in prostatic tissues of mice. Keeping in view its growth-promoting role, we suggest that S100A4 qualifies as an excellent candidate to be exploited for therapeutic agents to treat CaP in humans.

The size and morphology of chitosan-based nanoparticles encapsulating EGCG (CHI-EGCG-NPs) were examined by transmission electron microscopy (TEM). This technique allowed us to directly visualize the CHI-EGCG-NPs. It was found that the nanoparticles had a size of around 200 nm, which is further supported by what we observed earlier with our dynamic light scattering (DLS) data. Additionally, from the TEM picture, it is clear that the nanoparticles are spherical in shape. We also studied the release kinetics of EGCG from CHI-EGCG-NPs in simulated gastric juice and simulated intestinal fluid. It became clear from the data that the release of EGCG from these nanoparticles is very slow in acidic medium, even at 24 hrs only 10% of EGCG was released. On the other hand, release of intestinal fluid is much faster, and around 50% of EGCG was released in 24 hrs. We have earlier shown that treatment with CHI-EGCG-NPs (3 and 6 mg/kg body wt.) resulted in significant inhibition of tumor growth in athymic nude mice implanted with 22R 1 cells. Further extending this work, we report here that in tumor tissues of mice treated with both doses of CHI-EGCG-NPs as compared to group treated with EGCG and controls, there was significant (i) reduction in Ki-67 and proliferating cell nuclear antigen (PCNA) (ii) induction of poly (ADP-ribose) polymerases (PARP) cleavage, (iii) activation of caspases and, (iv) increase in the protein expression of Bax and decrease in Bcl2. Through this study, we propose a novel preventive and therapeutic modality using EGCG that addresses issues related to bioavailability, that is a major reason for its limited success in humans., The original document contains color images.

Imtiaz A Siddiqui, Vaqar M Adhami, Jean Christopher Chamcheu, Hasan MukhtarDepartment of Dermatology, University of Wisconsin, Madison, WI, USAAbstract: Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and treatment of the disease. Utilization of nanotechnology has enabled the development of devices in nanometer (nm) sizes which could be designed to encapsulate useful agents that have shown excellent results but otherwise are generally toxic due to the doses intended for extended use. In addition, examples are also available where these devices are easily conjugated with several purposeful moieties for better localization and targeted delivery. We introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention. This idea, which we termed as "nanochemoprevention," was subsequently exploited by several laboratories worldwide and has now become an advancing field in chemoprevention research. This review examines some of the up and coming applications of nanotechnology for cancer detection, imaging, treatment, and prevention. Further, we detail the current and future utilization of nanochemoprevention for prevention and treatment of cancer.Keywords: nanochemoprevention, cancer, nanotechnology

Microtubule associated proteins (MAP)-2 a component of the MAP family is a marker for neurons and its immuno-reactivity has been demonstrated in several neoplasms. We hypothesized that MAP-2 expression is deregulated in EGFR over-expressing breast cancers thus rendering them resistant to conventional therapy. Here we show that loss of MAP-2 expression in breast cancer cells during sustained activation of the EGFR results in resistance to chemotherapeutic drugs. We observed higher expression of MAP-2 in EGFR over-expressing cells than in non-EGFR over-expressing cells both at protein and mRNA levels. MCF-7 and MCF-10A cells were challenged with increasing doses of EGF (25-150 ng/ml) and examined for the expression of phosphorylated EGFR. We observed that expression of MAP-2 in cell lines challenged with EGF increased with increasing doses of EGF however its expression was almost completely lost at concentrations >100 ng/ml of EGF treatment. This observation suggested a possible mechanism of resistance in breast cancer patients with EGFR over-expression. We also found increasing resistance to growth inhibition by docetaxel in cells that were challenged with higher concentrations of EGFR (>50 ng/ml). This suggested that over expression of EGFR signaling in breast cancers could in fact be responsible for resistance to therapeutic agents. The loss of MAP-2 expression could have implications in treatment of breast cancers over-expressing the EGFR and exhibiting resistance to conventional therapy., The original document contains color images.