This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.cancerci.commostviewed/ Most viewed articles in last 30 days from Cancer Cell International (ISSN 1475-2867) published by BioMed Central Background: Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. Results: We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. Conclusion: This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect. http://www.cancerci.com/content/8/1/10 Zeina Saikali, Hemani Setya, Gurmit Singh and Sujata Persad Cancer Cell International 2008, 8:10 Number of accesses: 423 2008-07-03 doi:10.1186/1475-2867-8-10 Cancer Cell International 1475-2867 8 10 2008-07-03 Background: A localized hypoxic environment occurs during tumor growth necessitating an angiogenic response or tumor necrosis results. Novel cancer treatment strategies take advantage of tumor-induced vascularisation by combining standard chemotherapeutic agents with angiogenesis-inhibiting agents. This has extended the progression-free interval and prolonged survival in patients with various types of cancer. We postulated that the expression levels of angiogenesis-related proteins from various primary tumor cultures would be greater under hypoxic conditions than under normoxia. Methods: Fifty cell sources, including both immortalized cell lines and primary carcinoma cells, were incubated under normoxic conditions for 48 hours. Then, cells were either transferred to a hypoxic environment (1% O2) or maintained at normoxic conditions for an additional 48 hours. Cell culture media from both conditions was collected and analyzed via an ELISA-based assay to determine expression levels of 11 angiogenesis-related factors: VEGF, PDGF-AA, PDGF-AA/BB, IL-8, bFGF/FGF-2, EGF, IP-10/CXCL10, Flt-3 ligand, TGF-β1, TGF-β2, and TGF-β3. Results: A linear correlation between normoxic and hypoxic growth conditions exists for expression levels of eight of eleven angiogenesis-related proteins tested including: VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-β1, TGF-β2, EGF, and IP-10. For VEGF, the target of current therapies, this correlation between hypoxia and higher cytokine levels was greater in primary breast and lung carcinoma cells than in ovarian carcinoma cells or tumor cell lines. Of interest, patient cell isolates differed in the precise pattern of elevated cytokines. Conclusion: As linear correlations exist between expression levels of angiogenic factors under normoxic and hypoxic conditions in vitro, we propose that explanted primary cells may be used to probe the in vivo hypoxic environment. Furthermore, differential expression levels for each sample across all proteins examined suggests it may be possible to build a predictor for angiogenesis-related anticancer agents, as each sample has a unique expression profile. Further studies should be performed to correlate in vitro protein expression levels of angiogenesis-related factors with in vivo patient response. http://www.cancerci.com/content/8/1/11 Jamie M Heinzman, Stacey L Brower and Jason E Bush Cancer Cell International 2008, 8:11 Number of accesses: 385 2008-07-10 doi:10.1186/1475-2867-8-11 Cancer Cell International 1475-2867 8 11 2008-07-10 We describe the basic tenets of the current concepts of cancer biology, and review the recent advances on the suppressor role of senescence in tumor growth and the breakdown of this barrier during the origin of tumor growth. Senescence phenotype can be induced by (1) telomere attrition-induced senescence at the end of the cellular mitotic life span (MLS*) and (2) also by replication history-independent, accelerated senescence due to inadvertent activation of oncogenes or by exposure of cells to genotoxins. Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence. However, senescence as a tumor suppressor mechanism is a leaky process and senescent cells with mutations or epimutations in these genes escape mitotic catastrophe-induced cell death by becoming polyploid cells. These polyploid giant cells, before they die, give rise to several cells with viable genomes via nuclear budding and asymmetric cytokinesis. This mode of cell division has been termed neosis and the immediate neotic offspring the Raju cells. The latter inherit genomic instability and transiently display stem cell properties in that they differentiate into tumor cells and display extended, but, limited MLS, at the end of which they enter senescent phase and can undergo secondary/tertiary neosis to produce the next generation of Raju cells. Neosis is repeated several times during tumor growth in a non-synchronized fashion, is the mode of origin of resistant tumor growth and contributes to tumor cell heterogeneity and continuity. The main event during neosis appears to be the production of mitotically viable daughter genome after epigenetic modulation from the non-viable polyploid genome of neosis mother cell (NMC). This leads to the growth of resistant tumor cells. Since during neosis, spindle checkpoint is not activated, this may give rise to aneuploidy. Thus, tumor cells also are destined to die due to senescence, but may escape senescence due to mutations or epimutations in the senescent checkpoint pathway. A historical review of neosis-like events is presented and implications of neosis in relation to the current dogmas of cancer biology are discussed. Genesis and repetitive re-genesis of Raju cells with transient "stemness" via neosis are of vital importance to the origin and continuous growth of tumors, a process that appears to be common to all types of tumors. We suggest that unlike current anti-mitotic therapy of cancers, anti-neotic therapy would not cause undesirable side effects. We propose a rational hypothesis for the origin and progression of tumors in which neosis plays a major role in the multistep carcinogenesis in different types of cancers. We define cancers as a single disease of uncontrolled neosis due to failure of senescent checkpoint controls. http://www.cancerci.com/content/6/1/25 Rengaswami Rajaraman, Duane L Guernsey, Murali M Rajaraman and Selva R Rajaraman Cancer Cell International 2006, 6:25 Number of accesses: 310 2006-11-08 doi:10.1186/1475-2867-6-25 Cancer Cell International 1475-2867 6 25 2006-11-08 Brain tumors are now the leading cause of cancer-related deaths in children under age 15. Malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are desperately needed. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell populations to deliver therapeutic agents to the brain cancer cells. Current limitations of the stem cell therapy strategy include that stem cells are treated as a single entity and lack of uniform technology is adopted for selection of clinically relevant sub-populations of stem cells. Specifically, therapeutic success relies on the selection of a clinically competent stem cell population based on their capacity of targeting brain tumors. A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors is proposed to fill the gap in the current work flow of stem cell-based therapy. The organotypic slice platform has advantages of being mimic in vivo model, easier to manipulate to optimize parameters than in vivo models such as rodents and primates. This model serves as a framework to address the discrepancy between anticipated in vivo results and actual in vivo results, a critical barrier to timely progress in the field of the use of stem cells for the treatment of neurological disorders. http://www.cancerci.com/content/8/1/9 Shengwen Calvin Li and William Gunter Loudon Cancer Cell International 2008, 8:9 Number of accesses: 310 2008-05-22 doi:10.1186/1475-2867-8-9 Cancer Cell International 1475-2867 8 9 2008-05-22 For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future. http://www.cancerci.com/content/7/1/9 Jayesh Sagar, Boussad Chaib, Kevin Sales, Marc Winslet and Alexander Seifalian Cancer Cell International 2007, 7:9 Number of accesses: 283 2007-06-04 doi:10.1186/1475-2867-7-9 Cancer Cell International 1475-2867 7 9 2007-06-04 Cadherin cell adhesion molecules play an essential role in creating tight intercellular association and their loss has been correlated with poor prognosis in human cancer. Mutational activation of protein kinases and loss of cell adhesion occur together in human lung adenocarcinoma but how these two pathways interconnect is only poorly understood. Mouse models of human lung adenocarcinoma with oncogene expression targeted to subtypes of lung epithelial cells led to formation of adenomas or adenocarcinomas that lacked metastatic potential. Conditional genetic abrogation of epithelial tumour cell adhesion in mice with benign lung tumours induced by oncogenic RAF kinase has been demonstrated to induce intratumourous vascularization (angiogenic switch), progression to invasive adenocarcinoma and micrometastasis. Importantly, breaking cell adhesion in benign oncogene-driven lung tumour cells activated β-catenin signalling and induced the expression of several genes that are normally expressed in intestine rather than the lung. I will discuss potential routes to nuclear β-catenin signalling in cancer and how nuclear β-catenin may epigenetically alter the plasticity of tumour cells during malignant progression. http://www.cancerci.com/content/8/1/7 Rudolf Götz Cancer Cell International 2008, 8:7 Number of accesses: 263 2008-05-20 doi:10.1186/1475-2867-8-7 Cancer Cell International 1475-2867 8 7 2008-05-20 Background: 4-Hydroxycoumarin (4-HC) is a coumarin that lacks anticoagulant activity. 4-HC affects the cytoskeletal stability and decreases cell adhesion and motility of the melanoma cell line B16-F10. Together with integrins and other cytoskeletal proteins, paxillin participates in the regulation of cell adhesion and motility, acting as an adapter protein at focal adhesions. The present study determined the participation of paxillin in the reported effects of 4-HC and analyzed the role of paxillin in the formation of melanoma metastases. Results: 4-HC decreased protein and mRNA levels of α- and β-paxillin isoforms in B16-F10 cells. Paxillin downregulation correlated with an inadequate translocation of paxillin to focal adhesions and a reduced phosphotyr118-paxillin pool. Consequently, 4-HC altered paxillin-mediated signaling, decreasing the phosphorylation of FAK and the level of GTP-bound Rac-1. These results partially explain the mechanism of the previously reported effects of 4-HC. Additionally, we studied the effect of 4-HC on metastatic potential of B16-F10 cells through experimental metastasis assays. In vitro treatment of cells with 4-HC inhibited their capability to originate pulmonary metastases. 4-HC did not affect cell proliferation or survival, demonstrating that its antimetastatic effect is unrelated to changes on cell viability. We also studied the importance of paxillin in metastasis by transfecting melanoma cells with paxillin-siRNA. Transfection produced a modest reduction on metastatic potential, indicating that: i) paxillin plays a role as inducer of melanoma metastasis; and ii) paxillin downregulation is not sufficient to explain the antimetastatic effect of 4-HC. Therefore, we evaluated other changes in gene expression by differential display RT-PCR analysis. Treatment with 4-HC produced a downregulation of Adhesion Regulating Molecule-1 (ARM-1), which correlated with a decreased adhesion of melanoma cells to lung slides. Conclusion: This study shows that reduced paxillin expression is associated with the impaired cell adhesion and motility seen in 4-HC-treated cells and partially contributes to the antimetastatic effect of 4-HC. In contrast, the role of ARM-1 reduced expression in the effects of 4-HC is still to be clarified. The antimetastatic effect of 4-HC suggests that this compound, or others with similar mode of action, might be useful for the development of adjuvant therapies for melanoma. http://www.cancerci.com/content/8/1/8 Marco A Velasco-Velázquez, Nohemí Salinas-Jazmín, Nicandro Mendoza-Patiño and Juan J Mandoki Cancer Cell International 2008, 8:8 Number of accesses: 255 2008-05-20 doi:10.1186/1475-2867-8-8 Cancer Cell International 1475-2867 8 8 2008-05-20 Background: Human MCF-7 cells have been studied extensively as a model for breast cancer cell growth. Many reports have established that serum-starved MCF-7 cells can be induced to proliferate upon the sole addition of 17β-estradiol (E2). However, the extent of the mitogenic response to E2 varies in different MCF-7 strains and may even be absent. In this study we compared the E2-sensitivity of three MCF-7 laboratory strains. Results: The MCF-7S line is non-responsive to E2, the MCF-7 ATCC has an intermediate response to E2, while the MCF-7 NKI is highly E2-sensitive, although the levels and activities of the estrogen receptor (ER) are not significantly different. Both suramin and IGF type I receptor blocking antibodies are able to inhibit the mitogenic response to E2-treatment in MCF-7 ATCC and MCF-7 NKI cells. From this we conclude that E2-induced proliferation is dependent on IGF type I receptor activation in all three MCF-7 strains. Conclusions: The results presented in this article suggest that E2-responsiveness of MCF-7 cells is dependent on the secretion of an autocrine factor activating the IGF-IR. All three strains of MCF-7 breast cancer cells investigated do not respond to E2 if the IGF-RI-pathway is blocked. Generally, breast cancer therapy is targeted at inhibiting estrogen action. This study suggests that inhibition of IGF-action in combination with anti-estrogen-treatment may provide a more effective way in treatment or even prevention of breast cancer. http://www.cancerci.com/content/3/1/10 Irene HL Hamelers, Richard FMA van Schaik, John S Sussenbach and Paul H Steenbergh Cancer Cell International 2003, 3:10 Number of accesses: 224 2003-07-11 doi:10.1186/1475-2867-3-10 Cancer Cell International 1475-2867 3 10 2003-07-11 Background: Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis. Results: We determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined. Conclusion: Androgen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer. http://www.cancerci.com/content/8/1/3 Greg Shaw and David M Prowse Cancer Cell International 2008, 8:3 Number of accesses: 211 2008-03-18 doi:10.1186/1475-2867-8-3 Cancer Cell International 1475-2867 8 3 2008-03-18 Background: Pancratistatin (PST), a compound extracted from an Amaryllidaceae (AMD) family plant, has been shown to specifically induce apoptosis in cancer cells with no/minimal toxic effect on normal cells. A systematic synthetic approach has indicated that the minimum cytotoxic pharmacophore comprises the trans-fused b/c-ring system containing the 2, 3, 4-triol unit in the C-ring. To further explore the structure-activity relationship of this group of compounds we have investigated the anti-cancer efficacy and specificity of two PST-related natural compounds, AMD4 and AMD5. Both of these compounds lack the polyhydroxylated lycorane element of PST instead having a methoxy-substuituted crinane skeleton. Results: Our results indicate that AMD5 has efficacy and selectivity similar to PST, albeit at a 10-fold increased concentration. Interestingly AMD4 lacks apoptotic activity. Conclusion: Our results indicate that the phenanthridone skeleton in natural Amaryllidaceae alkaloids may be a significant common element for selectivity against cancer cells; furthermore, the configuration of the methoxy-side groups is responsible for higher binding affinity to the target protein/s thus making for a more efficient anti-cancer agent. http://www.cancerci.com/content/7/1/10 Carly Griffin, Natasha Sharda, Divya Sood, Jerald Nair, James McNulty and Siyaram Pandey Cancer Cell International 2007, 7:10 Number of accesses: 179 2007-06-05 doi:10.1186/1475-2867-7-10 Cancer Cell International 1475-2867 7 10 2007-06-05