Molecular Oncology RSS feed: Articles in Press. Molecular Oncology highlights new discoveries, approaches, as well as technical developments, in basic, clinical and discovery-driven translational research. Topics include: • Key biological processes such as cell cycle; DNA repair; apoptosis; invasion and metastasis; angiogenesis and lymphangiogenesis; cell signalling and interactive networks; immune response. • Emerging technologies (genomics, proteomics, functional genomics, metabolomics, tissue arrays, imaging), and model systems. •Biomarkers: diagnosis, prognosis, stratification and efficacy. • Cancer genetics, epigenetics, and genomic instability. • Minimal residual disease, pre-malignant lesions. • Cancer micro-environment. • Molecular pathology. • Tumour immunology. • Translational research. • Cancer therapy (target discovery, drug design, immunotherapy, combination therapies, resistance, and individualised treatment). • Chemotherapy, radiotherapy and surgery. • Clinical pharmacology. • Clinical trials, integration of basic science into cancer clinical trials. • Epidemiology and prevention. • Infrastructures (biobanks, databases, genomic resources). A main feature of the Journal is to provide an international forum for debating cancer issues, and for integrating the input of all the stakeholders. Coverage: Reviews, original articles, technical notes, editorials, news & views (commentary, science policy issues, ethical and legal issues, patient organisations, industry needs and alliances, regulatory issues, news items), letters to the editor, conference announcements, advertisements. Submitting Authors: Manuscripts can be submitted to Molecular Oncology at: http://ees.elsevier.com/molonc/ http://www.moloncol.org//inpress?rss=yesElsevier Inc.en © 2010 Federation of European Biochemical Societies. Published by Elsevier Inc. All rights reserved. Molecular Oncology1574-78912010-07-28 © 2010 Federation of European Biochemical Societies. Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.moloncol.org/article/PIIS1574789110000621/abstract?rss=yesSince the declaration of war on cancer some four decades ago, there has been an exponential growth in our understanding of the genetic and cellular mechanisms that contribute to cancer. As a consequence, a number of revolutionary drugs such as imatinib and trastuzumab have emerged, representing the first wave in a new era of targeted therapy. However, the range of new weapons with a proven track record in targeting cancer is surprisingly limited, highlighting the need for new approaches to improve cancer treatment and outcomes.Stem cells and cancer – The promise and puzzles - Uncorrected ProofJane E. Visvader, Geoffrey J. Lindeman10.1016/j.molonc.2010.07.001Molecular Oncology (2010)2010-07-28Molecular Oncology2010-07-28PREFACEhttp://www.moloncol.org/article/PIIS157478911000061X/abstract?rss=yesAbstract: Tissue stem cells have been linked to cancers of epithelial origin including the prostate. There are three relevant issues concerning stem cells and cancer that rely solely on functional studies: 1. Are there tissue-regenerating stem cells in the adult organ? 2. Can tissue-regenerating cells serve as targets for transformation? 3. Do primary tumors contain tumor-propagating (cancer stem) cells? We will review the recent literature with respect to these critical issues to provide a direct link between primitive cells and prostate cancer.Primitive origins of prostate cancer: In vivo evidence for prostate-regenerating cells and prostate cancer-initiating cells - Uncorrected ProofAndrew S. Goldstein, Tanya Stoyanova, Owen N. Witte10.1016/j.molonc.2010.06.009Molecular Oncology (2010)2010-07-23Molecular Oncology2010-07-23REVIEWhttp://www.moloncol.org/article/PIIS1574789110000591/abstract?rss=yesAbstract: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer where cells restricted to the ducts exhibit an atypical phenotype. Some DCIS lesions are believed to rapidly transit to invasive ductal carcinomas (IDCs), while others remain unchanged. Existing classification systems for DCIS fail to identify those lesions that transit to IDC. We studied gene expression patterns of 31 pure DCIS, 36 pure invasive cancers and 42 cases of mixed diagnosis (invasive cancer with an in situ component) using Agilent Whole Human Genome Oligo Microarrays 44k. Six normal breast tissue samples were also included as controls. qRT-PCR was used for validation. All DCIS and invasive samples could be classified into the “intrinsic” molecular subtypes defined for invasive breast cancer. Hierarchical clustering establishes that samples group by intrinsic subtype, and not by diagnosis. We observed heterogeneity in the transcriptomes among DCIS of high histological grade and identified a distinct subgroup containing seven of the 31 DCIS samples with gene expression characteristics more similar to advanced tumours. A set of genes independent of grade, ER-status and HER2-status was identified by logistic regression that univariately classified a sample as belonging to this distinct DCIS subgroup. qRT-PCR of single markers clearly separated this DCIS subgroup from the other DCIS, and contains samples from several histopathological and intrinsic molecular subtypes. The genes that differentiate between these two types of DCIS suggest several processes related to the re-organisation of the microenvironment. This raises interesting possibilities for identification of DCIS lesions both with and without invasive characteristics, which potentially could be used in clinical assessment of a woman’s risk of progression, and lead to improved management that would avoid the current over- and under-treatment of patients.Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer - Corrected ProofAslaug Aamodt Muggerud, Michael Hallett, Hilde Johnsen, Kristine Kleivi, Wenjing Zhou, Simin Tahmasebpoor, Rose-Marie Amini, Johan Botling, Anne-Lise Børresen-Dale, Therese Sørlie, Fredrik Wärnberg10.1016/j.molonc.2010.06.007Molecular Oncology (2010)2010-07-05Molecular Oncology2010-07-05http://www.moloncol.org/article/PIIS1574789110000608/abstract?rss=yesAn overview of Personal Profiles can be found at http://www.moloncol.org. Carlo M. CrocePersonal Profiles - Corrected Proof10.1016/j.molonc.2010.06.008Molecular Oncology (2010)2010-07-05Molecular Oncology2010-07-05EDITORIALhttp://www.moloncol.org/article/PIIS1574789110000542/abstract?rss=yesAbstract: Melanoma, like most cancers, is a disease that wreaks havoc mostly through its propensity to spread and establish secondary tumors at sites that are anatomically distant from the primary tumor. The consideration of models of cancer progression is therefore important to understand the essence of this disease. Previous work has suggested that melanoma may propagate according to a cancer stem cell (CSC) model in which rare tumorigenic and bulk non-tumorigenic cells are organized into stable hierarchies within tumors. However, recent studies using assays that are more permissive for revealing tumorigenic potential indicate that it will not be possible to cure patients by focusing research and therapy on rare populations of cells within melanoma tumors. Studies of the nature of tumorigenic melanoma cells reveal that these cells may gain a growth, metastasis and/or therapy resistance advantage by acquiring new genetic mutations and by reversible epigenetic mechanisms. In this light, efforts to link the phenotypes, genotypes and epigenotypes of melanoma cells with differences in their in vivo malignant potential provide the greatest hope of advancing the exciting progress finally being made against this disease.Progress in understanding melanoma propagation - Corrected ProofMark Shackleton, Elsa Quintana10.1016/j.molonc.2010.06.006Molecular Oncology (2010)2010-07-02Molecular Oncology2010-07-02REVIEWhttp://www.moloncol.org/article/PIIS1574789110000517/abstract?rss=yesAbstract: The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of the tumor. Although, the CSC hypothesis does not directly address the cell of origin of cancer, it is postulated that tissue-resident stem or progenitor cells are the most common targets of transformation. Clinically, CSCs are predicted to mediate tumor recurrence after chemo- and radiation-therapy due to the relative inability of these modalities to effectively target CSCs. If this is the case, then CSC must be efficiently targeted to achieve a true cure. Similarities between normal and malignant stem cells, at the levels of cell-surface proteins, molecular pathways, cell cycle quiescence, and microRNA signaling present challenges in developing CSC-specific therapeutics. Approaches to targeting CSCs include the development of agents targeting known stem cell regulatory pathways as well as unbiased high-throughput siRNA or small molecule screening. Based on studies of pathways present in normal stem cells, recent work has identified potential “Achilles heals” of CSC, whereas unbiased screening provides opportunities to identify new pathways utilized by CSC as well as develop potential therapeutic agents. Here, we review both approaches and their potential to effectively target breast CSC.Targeting breast cancer stem cells - Corrected ProofSean P. McDermott, Max S. Wicha10.1016/j.molonc.2010.06.005Molecular Oncology (2010)2010-06-24Molecular Oncology2010-06-24REVIEWhttp://www.moloncol.org/article/PIIS1574789110000505/abstract?rss=yesAbstract: Elevated cyclooxygenase-2 (COX-2) expression is observed in a variety of premalignant neoplastic tissues, suggesting COX-2 expression might serve as a potential indicator of subsequent tumor development. However, it has not been possible to compare the relationship between Cox-2 gene expression in premalignant lesions and their subsequent fate, because conventional studies require tissue destruction for analysis of gene expression. To monitor COX-2 expression non-invasively during tumor development, we created a Cox-2 luciferase knock-in mouse, Cox-2luc, in which the firefly luciferase coding region replaces the Cox-2 coding region. Luciferase activity was non-invasively, quantitatively and repeatedly monitored in Cox-2luc/+ mice subjected to DMBA/TPA multistage skin tumor induction. Luciferase activity is significantly higher in all papillomas than in surrounding skin. However, the magnitude of Cox-2 promoter-driven luciferase activity in small papillomas cannot predict subsequent papilloma regression or growth. Elevated Cox-2 promoter-driven luciferase signal can be detected when papillomas first become visible, but not before this time.Cox-2 gene expression in chemically induced skin papillomas cannot predict subsequent tumor fate - Corrected ProofTomo-o Ishikawa, Naveen K. Jain, Harvey R. Herschman10.1016/j.molonc.2010.06.004Molecular Oncology (2010)2010-06-23Molecular Oncology2010-06-23http://www.moloncol.org/article/PIIS1574789110000499/abstract?rss=yesAbstract: The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the “cytogenetic uniqueness” of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level.Cytogenomics of cancers: From chromosome to sequence - Corrected ProofAlain Bernheim10.1016/j.molonc.2010.06.003Molecular Oncology (2010)2010-06-21Molecular Oncology2010-06-21REVIEWhttp://www.moloncol.org/article/PIIS1574789110000487/abstract?rss=yesAbstract: Solid tumours are the most common cancers and represent a major therapeutic challenge. The cancer stem cell hypothesis is an attractive model to explain the functional heterogeneity commonly observed in solid tumours. It proposes a hierarchical organization of tumours, in which a subpopulation of stem cell-like cells sustains tumour growth, metastasis, and resistance to therapy. We will present the most recent advances in the cancer stem cell field, with particular emphasis on pancreatic cancer as one of the deadliest human tumours, and highlight open questions and caveats to be addressed in future studies. There is increasing evidence that solid tumours including pancreatic cancer are hierarchically organized and sustained by a distinct subpopulation of cancer stem cells. However, direct evidence for the validity of the cancer stem cell hypothesis in human pancreatic cancer remains controversial due to the limitations of xenograft models but supportive data are now emerging from mouse models using related or different sets of markers for the identification of murine cancer stem cells. Therefore, while the clinical relevance of cancer stem cells remains a fundamental issue for this rapidly emerging field, current findings clearly suggest that specific elimination of these cells is possible and therapeutically relevant. Targeting of signalling pathways that are of particular importance for the maintenance and the elimination of cancer stem cell as the proposed root of the tumour may lead to the development of novel treatment regimens for pancreatic cancer. Here we will review the current literature on pancreatic cancer stem cells and the future perspective of this rapidly emerging field.Pancreatic cancer stem cells – update and future perspectives - Corrected ProofEnza Lonardo, Patrick C. Hermann, Christopher Heeschen10.1016/j.molonc.2010.06.002Molecular Oncology (2010)2010-06-16Molecular Oncology2010-06-16REVIEWhttp://www.moloncol.org/article/PIIS1574789110000347/abstract?rss=yesAbstract: Cancer in the 21st century has become the number one cause of death in developed countries. Although much progress has been made in improving patient survival, tumour relapse is one of the important causes of cancer treatment failure. An early observation in the study of cancer was the heterogeneity of tumours. Traditionally, this was explained by a combination of genomic instability of tumours and micro environmental factors leading to diverse phenotypical characteristics. It was assumed that cells in a tumour have an equal capacity to propagate the cancer. This model is currently known as the stochastic model. Recently, the Cancer stem cell model has been proposed to explain the heterogeneity of a tumour and its progression. According to this model, the heterogeneity of tumours is the result of aberrant differentiation of tumour cells into the cells of the tissue the tumour originated from. Tumours were suggested to contain stem cell-like cells, the cancer stem cells or tumour-initiating cells, which are uniquely capable of propagating a tumour much like normal stem cells fuel proliferation and differentiation in normal tissue.In this review we discuss the normal stem cell biology of the stomach and intestine followed by both the stochastic and cancer stem cell models in light of recent findings in the gastric and intestinal systems. The molecular pathways underlying normal and tumourigenic growth have been well studied, and recently the stem cells of the stomach and intestine have been identified. Furthermore, intestinal stem cells were identified as the cells-of-origin of colon cancer upon loss of the tumour suppressor APC. Lastly, several studies have proposed the positive identification of a cancer stem cell of human colon cancer.At the end we compare the cancer stem cell model and the stochastic model. We conclude that clonal evolution of tumour cells resulting from genetic mutations underlies tumour initiation and progression in both cancer models. This implies that at any point during tumour development any tumour cell can revert to a cancer stem cell after having gained a clonal advantage over the original cancer stem cell. Therefore, these models represent two sides of the same coin.Stem cells and cancer of the stomach and intestine - Corrected ProofRobert G.J. Vries, Meritxell Huch, Hans Clevers10.1016/j.molonc.2010.05.001Molecular Oncology (2010)2010-06-14Molecular Oncology2010-06-14REVIEWhttp://www.moloncol.org/article/PIIS1574789110000359/abstract?rss=yesAbstract: Lung cancer is a devastating disease and a major therapeutic burden with poor survival rates. The discovery of rare cells with stem cell-like properties in solid tumours is emerging as an important area of cancer research and may help explain the resistance of these tumours to current therapeutics. Despite rapid developments in cancer stem cell research in other solid tumours, progress in the lung has been hampered by an incomplete understanding of the epithelial stem cell hierarchy, the heterogeneity of disease and the lack of a suitable in vivo transplantation model to assess stem cell behaviour. In this review we critically discuss what is currently known about the role of normal stem cells and cancer-initiating cells in lung tumour development, and briefly discuss strategies aimed at advancing the field of lung stem cell biology, with an emphasis on the design and manipulation of state-of-art mouse models.Cell of origin of lung cancer - Corrected ProofKate D. Sutherland, Anton Berns10.1016/j.molonc.2010.05.002Molecular Oncology (2010)2010-06-14Molecular Oncology2010-06-14REVIEWhttp://www.moloncol.org/article/PIIS1574789110000475/abstract?rss=yesAbstract: Transient or long-term quiescence, the latter referred to as dormancy are fundamental features of at least some adult stem cells. The status of dormancy is likely a critical mechanism for the observed resistance of normal HSCs and leukemic stem cells (LSCs) to anti-proliferative chemotherapy. Recent studies have revealed cytokines such as Interferon-alpha (IFNα) and G-CSF as well as arsenic trioxide (As2O3) to be efficient agents for promoting cycling of dormant HSCs and LSCs. Most interestingly, such cell cycle activated stem cells become exquisitely sensitive to killing by different chemotherapeutic agents, suggesting that dormant LSCs in patients may be targeted by a sequential two-step protocol involving an initial activation by IFNα, G-CSF or As2O3, followed by targeted chemotherapy.Targeting leukemic stem cells by breaking their dormancy - Corrected ProofMarieke Alida Gertruda Essers, Andreas Trumpp10.1016/j.molonc.2010.06.001Molecular Oncology (2010)2010-06-14Molecular Oncology2010-06-14REVIEWhttp://www.moloncol.org/article/PIIS157478911000030X/abstract?rss=yesAbstract: The KIT mutation D816V is associated with autonomous growth of mast cells (MC) and is detectable in most patients with systemic mastocytosis (SM), including cases with associated hematologic non-MC-lineage disease (AHNMD). Recently, KIT D816V was reported to be expressed in patients with acute myeloid leukemia (AML). However, it was not clarified whether these patients have co-existing occult SM. We investigated neoplastic cells in 101 patients with AML for expression of KIT D816V. In 7/101 patients (6.9%), KIT D816V was detectable. After a thorough histologic, molecular, and biochemical analysis, all 7 cases were found to have an associated SM, leading to the final diagnosis SM-AML. Microdissected tryptase+ MC displayed KIT D816V in all patients tested, whereas CD34+ blasts exhibited KIT D816V in only 2/4 patients. In one AML patient, SM without KIT D816V was detected. In all other patients, no associated SM was found, and leukemic blasts were negative for KIT D816V. In summary, our data show that KIT D816V in AML is highly associated with co-existing SM (SM-AML). Moreover, our data show that AML blasts may lack this transforming target-mutant, which may be important when considering the use of KIT D816V-targeting drugs for treatment of patients with KIT D816V-positive AML.High frequency of concomitant mastocytosis in patients with acute myeloid leukemia exhibiting the transforming KIT mutation D816V - Corrected ProofRobert Fritsche-Polanz, Marika Fritz, Andrea Huber, Karl Sotlar, Wolfgang R. Sperr, Christine Mannhalter, Manuela Födinger, Peter Valent10.1016/j.molonc.2010.04.008Molecular Oncology (2010)2010-05-03Molecular Oncology2010-05-03http://www.moloncol.org/article/PIIS1574789110000256/abstract?rss=yesThis article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.WITHDRAWN: Deconstructing the molecular portraits of breast cancer - Corrected ProofAleix Prat, Charles M. Perou10.1016/j.molonc.2010.04.003Molecular Oncology (2010)2010-04-26Molecular Oncology2010-04-26http://www.moloncol.org/article/PIIS1574789110000207/abstract?rss=yesAbstract: Activated Cdc42-associated Kinase, ACK1, is a non-receptor tyrosine kinase with numerous interacting partners, including Cdc42 and EGFR. Gene amplification and overexpression of ACK1 were found in many cancer types such as those of the lung and prostate. Previously, we identified both somatic- and germ line missense mutations in the ACK1 coding sequence, by surveying 261 cancer cell lines and 15 control tissues. Here, we verified and characterized the non-synonymous mutation, ACK-S985 N, located in the ubiquitin association domain of the protein.Both overexpression and silencing experiments in MCF7 and A498 cells, respectively, demonstrated a role of the ACK1 S985 N mutation in enhancing cell proliferation, migration and anchorage-independent growth as well as the epithelial–mesenchymal transition. Further, we showed that the ACK1 S985 N mutant is unable to bind ubiquitin, unlike the wild type kinase. This contributed to ACK1 protein stability and stabilized EGFR after EGF stimulation, thereby prolonging mitogenic signaling in cancer cells. In addition, the ACK1 S985 N-EGFR interaction is enhanced, but not the ubiquitination of the receptor. Intriguingly, silencing of ACK1 in A498 cells sensitized the renal carcinoma cells to gefitinib, against which they are otherwise resistant.The work demonstrates that other than gene amplification, a single somatic mutation in ACK1 can result in extended protein stability enabling the oncoprotein to exert its oncogenic function in tumor progression. It also provides a rationale to target ACK1 in combination with other chemotherapeutic drugs, such as EGFR inhibitors, to potentiate therapeutic action against resistant tumors.Somatic mutation in the ACK1 ubiquitin association domain enhances oncogenic signaling through EGFR regulation in renal cancer derived cells - Corrected ProofBoon Tin Chua, Shu Jing Lim, Su Chin Tham, Wei Jie Poh, Axel Ullrich10.1016/j.molonc.2010.03.001Molecular Oncology (2010)2010-03-22Molecular Oncology2010-03-22http://www.moloncol.org/article/PIIS1574789110000219/abstract?rss=yesAbstract: We document an EGFR mutation in a patient with papillary renal cell cancer with a history of multiple therapies, including interferon-alfa, interleukin-2, 5-fluorouracil, and interferon-alfa together with 13-cis-retinoic acid, to which floxuridine was later added, and thalidomide maintenance therapy for six years. We provide a succinct review of the PubMed-derived literature on EGFR mutations in diverse tumors, which indicates that a subset of patients with various tumor types may harbor EGFR mutations. A 32-year old woman with sporadic, metastatic papillary renal cancer was found to harbor an EGFR kinase domain mutation in addition to the MET kinase mutation typically found in this disease. Since lung cancer patients with EGFR mutations often respond well to EGFR inhibitor therapy and EGFR mutations occur in a variety of tumors, it should be worthwhile to assess EGFR status prospectively in other tumors and study the results of treatment with EGFR inhibitors in these patients.Epidermal growth factor receptor mutation and diverse tumors: Case report and concise literature review - Corrected ProofLakshmi Chintala, Razelle Kurzrock10.1016/j.molonc.2010.03.002Molecular Oncology (2010)2010-03-18Molecular Oncology2010-03-18REVIEW