Abstract. Breast cancer remains the leading cause of cancer mortality worldwide, despite a significant decline in death rates due to early detection. The majority of cancer mortalities are due to the metastasis of tumor cells to other organs. Metastasis or tumor cell dissemination occurs via the hematogenous and lymphatic systems. For many carcinomas, the dissemination of tumor cells via lymphatic drainage of the tumor is the most common metastatic route. Such lymphatic drainage collects at the regional lymph nodes and the dissection and pathological examination of these nodes for lodged cancer cells is the gold standard procedure to detect metastasis. The present report provides an overview of the lymphatic system and its clinical significance as a prognostic factor, in addition to the interactions between the primary tumor and its microenvironment, and the influence of genomic subtypes on the resulting organ-specific pattern of tumor cell dissemination. It also examines the seemingly protracted asymptomatic period, during which the disseminated cells remain dormant, leading to the manifestation of metastasis decades after the successful treatment of the primary tumor.

BackgroundComplex molecular events lead to development and progression of liver cirrhosis to HCC. Differentially expressed nuclear membrane associated proteins are responsible for the functional and structural alteration during the progression from cirrhosis to carcinoma. Although alterations/ post translational modifications in protein expression have been extensively quantified, complementary analysis of nuclear membrane proteome changes have been limited. Deciphering the molecular mechanism that differentiate between normal and disease state may lead to identification of biomarkers for carcinoma.ResultsMany proteins displayed differential expression when nuclear membrane proteome of hepatocellular carcinoma (HCC), fibrotic liver, and HepG2 cell line were assessed using 2-DE and ESI-Q-TOF MS/MS. From the down regulated set in HCC, we have identified for the first time a 15 KDa cytochrome b5A (CYB5A), ATP synthase subunit delta (ATPD) and Hemoglobin subunit beta (HBB) with 11, 5 and 22 peptide matches respectively. Furthermore, nitrosylation studies with S-nitrosocysteine followed by immunoblotting with anti SNO-cysteine demonstrated a novel and biologically relevant post translational modification of thiols of CYB5A in HCC specimens only. Immunofluorescence images demonstrated increased protein S-nitrosylation signals in the tumor cells and fibrotic region of HCC tissues. The two other nuclear membrane proteins which were only found to be nitrosylated in case of HCC were up regulated ATP synthase subunit beta (ATPB) and down regulated HBB. The decrease in expression of CYB5A in HCC suggests their possible role in disease progression. Further insight of the functional association of the identified proteins was obtained through KEGG/ REACTOME pathway analysis databases. String 8.3 interaction network shows strong interactions with proteins at high confidence score, which is helpful in characterization of functional abnormalities that may be a causative factor of liver pathology.ConclusionThese findings may have broader implications for understanding the mechanism of development of carcinoma. However, large scale studies will be required for further verification of their critical role in development and progression of HCC.

Identification of reliable non-invasive markers for the detection of invasive phenotype of urothelial carcinoma is needed. This study characterizes and compares protein expression profiles of adjacent non-neoplastic urothelium and invasive urothelial carcinoma to identify biomarkers for early detection of de novo bladder cancer. Differences in protein expression between adjacent non-neoplastic and high-grade, stage T4, grade 3 invasive urothelial carcinoma tissues were investigated using 2-DE, MALDI-TOF-MS, and data processing. Ingenuity Pathway Analysis (IPA) was applied to examine the biological mechanisms represented by the altered proteins. The 2-DE of the adjacent non-neoplastic urothelium and invasive urothelial carcinoma showed reproducibly similar proteomic mapping for each group distinguishing adjacent non-neoplastic urothelium from invasive urothelial carcinoma. Twenty-one proteins were altered in expression and one of these proteins, Choroideremia-like protein (CHML) was significantly overexpressed (p<0.005) and therefore was analyzed further using IHC and Western blot. Urothelial carcinoma presented an elevated expression of CHML but not adjacent non-neoplastic or normal bladder tissues. IPA revealed the involvement of CHML in cell morphology, cellular assembly, and organization. Further investigation is warranted to elucidate the biological significance of CHML and to validate its role as a biomarker for early detection of invasive urothelial carcinoma de novo.

Urinary bladder cancer is the fifth most common cancer in the United States. The National Cancer Institute estimates that the incidence rates will be 68 810 and the mortality rate will be 14 100 in the year 2008. Although the gold standards cytology and cystoscopy are specific for diagnosing bladder cancer, the former lacks the sensitivity to detect low-grade tumors and the latter is very invasive and expensive. Therefore, scientists are interested in identifying reliable non-invasive biomarkers that could be utilized in screening, leading to early detection and/or in predicting the progression of superficial tumors to invasive higher-stage lesions with high specificity and sensitivity. Several biomarkers that indicate changes in the expression of proteins associated with increased risk have been identified. The purpose of this analysis is to provide an overview of the studies that have been conducted during the last decade that identify diagnostic and prognostic biomarkers via proteomic and genomic advancements.

Previously, it has to be acknowledged that overexpressed heat shock protein B27 (HSPB27) have been implicated in the etiology of wide range of human cancers. However, the molecular mechanism leading to the disease initiation to progression in liver cancer is still unknown. Present work was undertaken to investigate the differentially expressed HSPB27 in association with those damages that lead to liver cancer development. For the identification of liver cancer biomarker, samples were subjected to comparative proteomic analysis using two-dimensional gel electrophoresis (2-DE) and were further validated by Western blot and immunohistochemical analysis. After validation, in silico studies were applied to demonstrate the significantly induced phosphorylated and S-nitrosylated signals. The later included the interacting partner of HSPB27, i.e., mitogen-activated protein kinase-3 and 5 (MAPK3 and 5), ubiquitin C (UBC), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mitogen-activated protein kinase 14 (MAPK14), and tumor protein p53 (TP53), which bestowed with critical capabilities, namely, apoptosis, cell cycling, stress activation, tumor suppression, cell survival, angiogenesis, proliferation, and stress resistance. Taking together, these results shed new light on the potential biomarker HSPB27 that overexpression of HSPB27 did lead to upregulation of their interacting partner that together demonstrate their possible role as a novel tumor progressive agent for the treatment of metastasis in liver cancer. HSPB27 is a promising diagnostic marker for liver cancer although further large-scale studies are required. Also, molecular profiling may help pave the road to the discovery of new therapies.