Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
BBA - Reviews on Cancer (v.1785, #2)
Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases by Thomas J. Wilson; Rakesh K. Singh (pp. 85-95).
As cells undergo oncogenic transformation and as malignant cells arrive at metastatic sites, a complex interplay occurs with the surrounding stroma. This dialogue between the tumor and stroma ultimately dictates the success of the tumor cells in the given microenvironment. As a result, understanding the molecular mechanisms at work is important for developing new therapeutic modalities. Proteases are major players in the interaction between tumor and stroma. This review will focus on the role of proteases in modulating tumor–stromal interactions of both primary breast and prostate tumors as well as at bone metastatic sites in a way that favors tumor growth.
Keywords: Proteases; Tumor–stromal interaction; Tumor progression; Bone metastasis
Taxanes, microtubules and chemoresistant breast cancer by Barbara T. McGrogan; Breege Gilmartin; Desmond N. Carney; Amanda McCann (pp. 96-132).
The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.
Keywords: Breast cancer; Taxanes; Microtubules; Chemoresistance; Spindle assembly checkpoint (SAC); Tubulin; BRCAl; Mitotic assembly deficient protein 2 (MAD2)
Genetics and epigenetics of renal cell cancer by Marcella M.L. Baldewijns; Iris J.H. van Vlodrop; Leo J. Schouten; Patricia M.M.B. Soetekouw; Adriaan P. de Bruïne; Manon van Engeland (pp. 133-155).
Renal cell carcinoma (RCC) is not a single disease, but comprises a group of tumors of renal epithelial origin, each with a different histology, displaying a different clinical course and caused by different genetic alterations. Since cure rates are inversely associated with stage and response to the available treatment regimes is limited to a subgroup of patients, diagnostic methods facilitating early detection and new therapeutic modalities are necessary. Increased knowledge of the underlying pathophysiology of RCC has resulted in the identification of genetic alterations involved in renal cell cancer carcinogenesis. Promising agents to target these pathways, especially the angiogenesis pathway, are being developed, some of which are already standard of care. In addition to genetics, knowledge on epigenetics in the process of renal tumorigenesis has been significantly increased in the last decades. Epigenetics will play an increasing role in the development of new therapeutic modalities and may deliver new prognostic and early diagnostic markers.In this review we discuss the background of RCC and the clinical applications of RCC genetics and epigenetics.
Keywords: Renal cell carcinoma; Kidney cancer; Genetics; Epigenetics; DNA methylation
Prostatic preneoplasia and beyond by A.M. Joshua; A. Evans; T. Van der Kwast; M. Zielenska; A.K. Meeker; A. Chinnaiyan; J.A. Squire (pp. 156-181).
Prostate cancer is a heterogeneous neoplasm both with regard to its development, molecular abnormalities and clinical course. For example, in the United States, 1 in 6 men is diagnosed with prostate cancer whilst only 1 in 34 dies of metastatic disease [A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M.J. Thun, Cancer Statistics, 2007, CA Cancer J. Clin. 57 (2007) 43–66]. In this review, we summarise novel understandings of the early molecular events in prostatic carcinogenesis that may underlie both the molecular and clinical heterogeneity. Issues covered include those related to stem cells and embryonic signalling, oncogene/tumor suppressor abnormalities, androgen signalling, apoptosis and the nature of tumor–stromal interactions. Emphasis is placed on signalling pathway abnormalities, their causation, consequences and interactions. For example, genomic abnormalities involving the TMPRSS2–ETS and PTEN loci and the resulting signalling effects suggest the importance of genomic instability as a crucial factor in the emergence of this neoplasm. Together with new insights into signalling pathways consequent to abnormalities such as these, a greater understanding of the pathophysiology involved in prostatic carcinogenesis will lead to targeted approaches for both therapy and chemoprevention in the future.
Keywords: Prostatic neoplasms; Disease progression; Carcinogenesis; Cancer genetics
Dissecting lipid raft facilitated cell signaling pathways in cancer by Samir Kumar Patra (pp. 182-206).
Cancer is one of the most devastating disorders in our lives. Higher rate of proliferation than death of cells is one of the essential factors for development of cancer. The dynamicity of cell membrane plays some vital roles in cell survival and cell death, including protection, endocytosis, signaling, and increases in mechanical stability during cell division, as well as decrease of shear forces during separation of two cells after division, and cell separation from tissues for cancer metastasis. Within the membrane, there are specialized domains, known as lipid rafts. A raft can coordinate various signaling pathways. Recent data on the proteomics of lipid rafts/caveolae have highlighted the enigmatic role of various signaling proteins in cancer development. Analysis of these data of raft proteome from various tumors, cancer tissues, and cell lines cultured without and with therapeutic agents, as well as from model rafts revealed that there may be two subsets of raft assemblage in cell membrane. One subset of raft is enriched with cholesterol–sphingomyeline–ganglioside–cav-1/Src/EGFR (hereafter, “chol-raft”) that is involved in normal cell signaling, and when dysregulated promotes cell transformation and tumor progression; another subset of raft is enriched with ceramide–sphingomyeline–ganglioside–FAS/Ezrin (hereafter, “cer-raft”) that generally promotes apoptosis. In view of this, and to focus insight into the cancer cell physiology caused by the lipid rafts mediated signals and their receptors, and the downstream transmitters, either proliferative (for example, EGF and EGFR) or death-inducing (for example, FASL and FAS), and the precise roles of some therapeutic drugs and endogenous acid sphingomylenase in this scenario in in situ transformation of “chol-raft” into “cer-raft” are summarized and discussed in this contribution.
Keywords: Cancer; Catenin; Caveolin-1; CD44; Ceramide; EGFR; Cholesterol; E-cadherin; Ezrin; FAS/CD95; FASL; Focal adhesion kinase; H-ras; Integrin; Lipid rafts; Matrix metalloproteinases (MMPs); Proteomics; Signal transduction; Sphingomyelin; uPA; uPAR; MAP kinaseAbbreviations; Acid sphingomyelinase; ASMase; Activator protein-1; AP-1; Caveolin-1; cav-1; Ceramide; Cer; Cholesterol; Chol; Extracellular matrix; ECM; E-cadherin; E-cad; Endoplasmic reticulum; ER; Epidermal growth factor; EGF; EGF receptor; EGFR; Extracellular signal-regulated kinase; ERK; FAS antigen; FAS; FAS associated death domain; FADD; FAS ligand; FASL, Death-inducing signaling complex, DISC; Focal adhesion kinase; FAK; Glycosyl phosphatidyl inositol; GPI; Insulin like growth factor; IGF; Matrix metalloproteinases; MMPs; Mitogen activated protein kinase; MAPK; MAP/ERK kinase 1/2; MEK1/2; Nuclear factor-kB; NF-kB; Phosphoinositide 3-kinase; PI3K; Plasma membranes; PM; Receptor tyrosine kinases; RTKs; Retinoic acid; RA; RA receptor; RAR; Sentinel lymph nodes; SLN; Sphingomyelin; SM; Thrombospondine 2; THBS2; Urokinase type plasminogen activator (uPA); uPA receptor (uPAR)
DNp73 a matter of cancer: Mechanisms and clinical implications by Sven Buhlmann; Brigitte M. Pützer (pp. 207-216).
The p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis, and chemosensitivity of tumors. NH2-terminally truncated p73 (referred to as DNp73) acts as a potent inhibitor of all these tumor suppressor properties, implying that it has oncogenic functions in human tumorigenesis. This was favored by the observation that high DNp73 expression levels in a variety of cancers are associated with adverse clinico-pathological characteristics and the response failure to chemotherapy. The actual challenge is the deciphering of the molecular mechanisms by which DNp73 promotes malignancy and to unravel the regulatory pathways for controlling TP73 isoform expression. This review is focused on recent findings leaving no doubt that N-terminally truncated p73 proteins are operative during oncogenesis, thus underscoring its significance as a marker for disease severity in patients and as target for cancer therapy.
Keywords: DNp73; Oncogene; Tumorigenesis; Tumor suppressor pathways; Differentiation; Cancer
Oncolytic virotherapy: Molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses by Z. Sheng Guo; Stephen H. Thorne; David L. Bartlett (pp. 217-231).
Tremendous advances have been made in developing oncolytic viruses (OVs) in the last few years. By taking advantage of current knowledge in cancer biology and virology, specific OVs have been genetically engineered to target specific molecules or signal transduction pathways in cancer cells in order to achieve efficient and selective replication. The viral infection and amplification eventually induce cancer cells into cell death pathways and elicit host antitumor immune responses to further help eliminate cancer cells. Specifically targeted molecules or signaling pathways (such as RB/E2F/p16, p53, IFN, PKR, EGFR, Ras, Wnt, anti-apoptosis or hypoxia) in cancer cells or tumor microenvironment have been studied and dissected with a variety of OVs such as adenovirus, herpes simplex virus, poxvirus, vesicular stomatitis virus, measles virus, Newcastle disease virus, influenza virus and reovirus, setting the molecular basis for further improvements in the near future. Another exciting new area of research has been the harnessing of naturally tumor-homing cells as carrier cells (or cellular vehicles) to deliver OVs to tumors. The trafficking of these tumor-homing cells (stem cells, immune cells and cancer cells), which support proliferation of the viruses, is mediated by specific chemokines and cell adhesion molecules and we are just beginning to understand the roles of these molecules. Finally, we will highlight some avenues deserving further study in order to achieve the ultimate goals of utilizing various OVs for effective cancer treatment.
Keywords: Cancer; Oncolytic virus; Oncolysis; Selective replication; Target molecule; Signaling pathway; Chemokine; Drug
Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer by Jacqueline M. Lafky; Jason A. Wilken; Andre T. Baron; Nita J. Maihle (pp. 232-265).
The ERBB or EGF receptor (EGFR) proto-oncogene family, which consists of four structurally-related transmembrane receptors (i.e., EGFR, ErbB2, ErbB3, and ErbB4), plays an etiological role in the molecular pathogenesis of cancer and is a key therapeutic target in many types of cancer, including ovarian cancer. These ErbB/EGF receptor tyrosine kinases play important physiologic roles in cell proliferation, survival, adhesion, motility, invasion, and angiogenesis. It is, therefore, not surprising that gene amplification, genetic mutation, and altered transcription/translation result in aberrant ErbB/EGF receptor expression and/or signal transduction, contributing to the development of malignant transformation. Clinically, the diagnostic, prognostic, and theragnostic significance of any single ErbB receptor and/or ErbB ligand is controversial, but generally, ErbB receptor overexpression has been correlated with poor prognosis and decreased therapeutic responsiveness in ovarian cancer patients. Thus, anticancer agents targeting ErbB/EGF receptors hold great promise for personalized cancer treatment. Yet, challenges remain in designing prospective clinical trials to assess the clinical utility of ErbB receptors and their ligands to diagnose cancer; to predict progression-free and overall survival, therapeutic responsiveness, and disease recurrence; and to monitor treatment responsiveness. Here, we review the tissue expression and serum biomarker studies that have evaluated the diagnostic, prognostic, and theragnostic utility of ErbB/EGF receptors, their circulating soluble isoforms (sEGFR/sErbBs), and their cognate ligands in ovarian cancer patients.
Keywords: Ovarian cancer; ErbB receptors; Soluble ErbB receptors; EGF family; EGF receptor; HER family; Receptor tyrosine kinases; TGF-α; Amphiregulin; Heregulins; Neuregulins; Biomarkers