Molecular Oncology
1574-7891
1878-0261
Hà Lan
Cơ quản chủ quản: WILEY , John Wiley and Sons Ltd
Lĩnh vực:
GeneticsOncologyMedicine (miscellaneous)Molecular MedicineCancer Research
Phân tích ảnh hưởng
Thông tin về tạp chí
Molecular Oncology is a monthly online-only Open Access journal that highlights new discoveries, approaches, as well as technical developments, in basic, clinical and discovery-driven translational cancer research. The emphasis is on work that significantly advances our understanding of disease processes leading to human tumour development and/or establishes novel concepts of clear clinical significance in diagnosis, prognosis and prevention strategies for cancer patients. Submissions that meet the high standards of the journal are sent for rigorous, single-blind peer review by experts in the field. Topics include, but are not limited to: 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. Molecular epidemiology.
Các bài báo tiêu biểu
Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells Poly‐ADP‐ribose‐polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication‐dependent and more profound in HR‐deficient tumors. Here, we present a new mode of PARPi‐mediated radiosensitization which was observed in four out of six HR‐proficient tumor cell lines (responders ) investigated, but not in normal cells. This effect is replication‐independent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB‐repair is switched to PARP1‐dependent end‐joining (PARP1‐EJ), as evident by (i) the significant increase in the number of residual γH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end‐joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1‐EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy.
Tập 8 Số 8 - Trang 1616-1625 - 2014
Emerging functions of the <scp>EGFR</scp> in cancer The physiological function of the epidermal growth factor receptor (EGFR ) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus , but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.
Tập 12 Số 1 - Trang 3-20 - 2018
Claudin‐2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences Background Predicting any future metastatic site of early‐stage breast cancer is important as it significantly influences the prognosis of advanced disease. This study aimed at investigating the potential of claudin‐2, over‐expressed in breast cancer liver metastases, as a biomarker for predicting liver metastatic propensity in primary breast cancer. Methods Claudin‐2 expression was analyzed in two independent cohorts. Cohort 1 included 304 women with metastatic breast cancer diagnosed between 2002 and 2007, while cohort 2 included 237 premenopausal women with early‐stage node‐negative breast cancer diagnosed between 1991 and 1994. Global transcriptional profiling of fine‐needle aspirates from metastases was performed, followed by immunohistochemical analyses in archival primary tumor tissue. Associations between claudin‐2 expression and relapse site were assessed by univariable and multivariable Cox regression models including conventional prognostic factors. Two‐sided statistical tests were used. Results
CLDN2 was significantly up‐regulated (P < 0.001) in liver metastases compared to other metastatic sites. Claudin‐2 protein was more frequently expressed in primary tumors from patients who subsequently developed liver metastases (P = 0.02) and high expression was associated with a shorter metastasis‐free interval (cohort 1, HR = 1.4, 95% CI = 1.0–1.9; cohort 2, HR = 2.2, 95% CI = 1.3–3.5). Specifically, a significantly shorter interval between primary tumor diagnosis and liver‐specific recurrence was observed among patients with high levels of claudin‐2 expression in the primary tumor (cohort 1, HR = 2.3, 95% CI = 1.3–3.9). Conclusion These results suggest a novel role for claudin‐2 as a prognostic biomarker with the ability to predict not only the likelihood of a breast cancer recurrence, but more interestingly, the liver metastatic potential of the primary tumor.
Tập 8 Số 1 - Trang 119-128 - 2014
Non‐coding RNAs in cancer initiation and progression and as novel biomarkers Cancer represents a complex group of heterogeneous diseases. While many cancers share fundamental biological processes (hallmarks of cancer) necessary for their development and progression, cancers also distinguish themselves by their dependence on distinct oncogenic pathways. Over the last decade, targeted therapies have been introduced to the clinic with variable success. In truth, single targeted therapies may be successful in only a subset of malignancies but insufficient to address malignancies that often rely on multiple pathways, thus evading single targeted agents. Investigators have recently identified potentially functional components of the human genome that were previously thought to have no biological function. This discovery has added to the already established complexity of gene regulation in the pathogenesis of cancer. Non‐coding RNAs represent key regulators of gene expression. Improved knowledge of their biogenesis and function may in turn lead to a better understanding of the heterogeneity of malignancies and eventually be leveraged as diagnostic, prognostic and therapeutic targets. MicroRNAs (miRNAs or miRs) for example, have the capacity for the regulation of multiple genes and thus redirection or reprogramming of biological pathways. However, several other members of the non‐coding RNA family may be of equal biological relevance. In this review, we provide a perspective on emerging concepts in the clinical application of miRNA and other non‐coding RNAs as biomarkers in cancer with an eye on the eventual integration of both miRNA and other non‐coding RNA biology into our understanding of cancer pathogenesis and treatment.
Tập 5 Số 6 - Trang 483-491 - 2011
The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.
Tập 6 - Trang 111-127 - 2012
Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: The role of massively parallel sequencing In this proof‐of‐principle study, we sought to define whether targeted capture massively parallel sequencing can be employed to determine the origin of metastatic deposits in cases of synchronous primary malignancies and metastases in distinct anatomical sites. DNA samples extracted from synchronous tumor masses in the breast, adnexal, and pelvic‐peritoneal regions from a 62‐year‐old BRCA1 germline mutation carrier were subjected to targeted massively parallel sequencing using a platform comprising 300 cancer genes known to harbor actionable mutations. In addition to BRCA1 germline mutations, all lesions harbored somatic loss of the BRCA1 wild‐type allele and TP53 somatic mutations. The primary breast cancer displayed a TP53 frameshift (p.Q317fs) mutation, whereas and the adnexal lesion harbored a TP53 nonsense (p.R213*) mutation, consistent with a diagnosis of two independent primary tumors (i.e. breast and ovarian cancer). The adnexal tumor and all pelvic‐peritoneal implants harbored identical TP53 (p.R213*) and NCOA2 (p.G952R) somatic mutations. Evidence of genetic heterogeneity within and between lesions was observed, both in terms of somatic mutations and copy number aberrations. The repertoires of somatic genetic aberrations found in the breast, ovarian, and pelvic‐peritoneal lesions provided direct evidence in support of the distinct origin of the breast and ovarian cancers, and established that the pelvic‐peritoneal implants were clonally related to the ovarian lesion. These observations were consistent with those obtained with immunohistochemical analyses employing markers to differentiate between carcinomas of the breast and ovary, including WT1 and PAX8. Our results on this case of a patient with BRCA1‐mutant breast and ovarian cancer demonstrate that massively parallel sequencing may constitute a useful tool to define the relationship, clonality and intra‐tumor genetic heterogeneity between primary tumor masses and their metastatic deposits in patients with multiple primary malignancies and synchronous metastases.
Tập 8 - Trang 150-158 - 2014
Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships Purpose: Lobular carcinoma in situ (LCIS) has been proposed as a non‐obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing.Methods: DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair‐related genes. Single nucleotide variants and insertions and deletions were identified using state‐of‐the‐art bioinformatics approaches.Results: The constellation of somatic mutations found in LCIS (n = 34) and ILC (n = 21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1).Conclusion: LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS–LCIS and LCIS–ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non‐obligate precursors of ILC.
Tập 10 - Trang 360-370 - 2016
Targeting immunogenic cell death in cancer Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage‐associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor‐specific immune responses, thus eliciting long‐term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. Remarkably, subcutaneous injection of dying tumor cells undergoing ICD has been shown to provoke anticancer vaccine effects in vivo . DAMPs include the cell surface exposure of calreticulin (CRT) and heat‐shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high‐mobility group box‐1 (HMGB1), type I IFNs and members of the IL‐1 cytokine family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy.
Tập 14 Số 12 - Trang 2994-3006 - 2020
Combination therapy induces unfolded protein response and cytoskeletal rearrangement leading to mitochondrial apoptosis in prostate cancer
Tập 10 - Trang 949-965 - 2016
Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history.
Tập 9 - Trang 270-281 - 2015