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Cancers, Volume 9, Issue 8 (August 2017) – 15 articles

Cover Story (view full-size image): Metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination of shed tumor cells and multicellular aggregates that avoid anoikis and ultimately adhere to and anchor within the submesothelial lining of the peritoneal cavity to generate widely disseminated metastases. This unique microenvironment is highly permissive for phenotypic plasticity. In this review, we summarize current knowledge of EOC heterogeneity in the context of epithelial:mesenchymal and mesenchymal:epithelial transition (EMT, MET), outline regulators of this process, address controversies in EMT and chemoresistance, and highlight computational modeling approaches toward a better understanding EMT/MET in EOC. View this paper
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577 KiB  
Review
Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors
by Joline S. J. Lim and David S. P. Tan
Cancers 2017, 9(8), 109; https://doi.org/10.3390/cancers9080109 - 22 Aug 2017
Cited by 37 | Viewed by 14292
Abstract
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors [...] Read more.
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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4177 KiB  
Article
National and Subnational Population-Based Incidence of Cancer in Thailand: Assessing Cancers with the Highest Burdens
by Shama Virani, Surichai Bilheem, Wasan Chansaard, Imjai Chitapanarux, Karnchana Daoprasert, Somsak Khuanchana, Atit Leklob, Donsuk Pongnikorn, Laura S. Rozek, Surattaya Siriarechakul, Krittika Suwanrungruang, Sukit Tassanasunthornwong, Patravoot Vatanasapt and Hutcha Sriplung
Cancers 2017, 9(8), 108; https://doi.org/10.3390/cancers9080108 - 17 Aug 2017
Cited by 90 | Viewed by 15737
Abstract
In Thailand, five cancer types—breast, cervical, colorectal, liver and lung cancer—contribute to over half of the cancer burden. The magnitude of these cancers must be quantified over time to assess previous health policies and highlight future trajectories for targeted prevention efforts. We provide [...] Read more.
In Thailand, five cancer types—breast, cervical, colorectal, liver and lung cancer—contribute to over half of the cancer burden. The magnitude of these cancers must be quantified over time to assess previous health policies and highlight future trajectories for targeted prevention efforts. We provide a comprehensive assessment of these five cancers nationally and subnationally, with trend analysis, projections, and number of cases expected for the year 2025 using cancer registry data. We found that breast (average annual percent change (AAPC): 3.1%) and colorectal cancer (female AAPC: 3.3%, male AAPC: 4.1%) are increasing while cervical cancer (AAPC: −4.4%) is decreasing nationwide. However, liver and lung cancers exhibit disproportionately higher burdens in the northeast and north regions, respectively. Lung cancer increased significantly in northeastern and southern women, despite low smoking rates. Liver cancers are expected to increase in the northern males and females. Liver cancer increased in the south, despite the absence of the liver fluke, a known factor, in this region. Our findings are presented in the context of health policy, population dynamics and serve to provide evidence for future prevention strategies. Our subnational estimates provide a basis for understanding variations in region-specific risk factor profiles that contribute to incidence trends over time. Full article
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626 KiB  
Review
ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice
by Paul Hofman
Cancers 2017, 9(8), 107; https://doi.org/10.3390/cancers9080107 - 12 Aug 2017
Cited by 44 | Viewed by 10657
Abstract
Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to [...] Read more.
Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient’s sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
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219 KiB  
Review
ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients
by Paul Hofman
Cancers 2017, 9(8), 106; https://doi.org/10.3390/cancers9080106 - 12 Aug 2017
Cited by 19 | Viewed by 4906
Abstract
Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due [...] Read more.
Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due to different resistance mechanisms including mutations in the tyrosine kinase domain of echinoderm microtubule-associated protein-like 4 (EML44)-ALK. The liquid biopsy concept has recently radically changed the clinical care of NSCLC patients, in particular for those harboring an epidermal growth factor receptor (EGFR) gene mutation. Therefore, liquid biopsy is an alternative or complementary method to tissue biopsy for the detection of some resistance mutations in EGFR arising during tyrosine kinase inhibitor treatment. Moreover, in some frail patients, or if the tumor lesion is not accessible to a tissue biopsy, a liquid biopsy can also detect some activating mutations in EGFR on initial assessment. Recent studies have evaluated the possibility of also using a liquid biopsy approach to detect an ALK rearrangement and/or the emergence during inhibitor treatment of some resistance mutations in ALK. These assessments can be performed by studying circulating tumor cells by fluorescent in situ hybridization and by immunocytochemistry and/or after the isolation of RNA from plasma samples, free or associated with platelets. Thus, the liquid biopsy may be a complementary or sometimes alternative method for the assessment of the ALK status in certain NSCLC patients, as well as a non-invasive approach for early detection of ALK mutations. In this review, we highlight the current data concerning the role of the liquid biopsy for the ALK status assessment for NSCLC patients, and we compare the different approaches for this evaluation from blood samples. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
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Review
The Role of Cancer-Derived Exosomes in Tumorigenicity & Epithelial-to-Mesenchymal Transition
by Robert H. Blackwell, Kimberly E. Foreman and Gopal N. Gupta
Cancers 2017, 9(8), 105; https://doi.org/10.3390/cancers9080105 - 10 Aug 2017
Cited by 66 | Viewed by 6586
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells lose their basement membrane interaction and acquire a more migratory, mesenchymal phenotype. EMT has been implicated in cancer cell progression, as cells transform and increase motility and invasiveness, induce angiogenesis, and metastasize. Exosomes [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells lose their basement membrane interaction and acquire a more migratory, mesenchymal phenotype. EMT has been implicated in cancer cell progression, as cells transform and increase motility and invasiveness, induce angiogenesis, and metastasize. Exosomes are 30–100 nm membrane-bound vesicles that are formed and excreted by all cell types and released into the extracellular environment. Exosomal contents include DNA, mRNA, miRNA, as well as transmembrane- and membrane-bound proteins derived from their host cell contents. Exosomes are involved in intercellular signaling, both by membrane fusion to recipient cells with deposition of exosomal contents into the cytoplasm and by the binding of recipient cell membrane receptors. Recent work has implicated cancer-derived exosomes as an important mediator of intercellular signaling and EMT, with resultant transformation of cancer cells to a more aggressive phenotype, as well as the tropism of metastatic disease in specific cancer types with the establishment of the pre-metastatic niche. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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2120 KiB  
Review
Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer
by Yuliya Klymenko, Oleg Kim and M. Sharon Stack
Cancers 2017, 9(8), 104; https://doi.org/10.3390/cancers9080104 - 09 Aug 2017
Cited by 74 | Viewed by 16443
Abstract
Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular [...] Read more.
Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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6786 KiB  
Review
Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review
by Ryuya Yamanaka, Eisuke Abe, Toshiteru Sato, Azusa Hayano and Yasuo Takashima
Cancers 2017, 9(8), 103; https://doi.org/10.3390/cancers9080103 - 08 Aug 2017
Cited by 31 | Viewed by 6523
Abstract
Pituitary adenomas are often treated with radiotherapy for the management of tumor progression or recurrence. Despite the improvement in cure rates, patients treated by radiotherapy are at risk of development of secondary malignancies. We conducted a comprehensive literature review of the secondary intracranial [...] Read more.
Pituitary adenomas are often treated with radiotherapy for the management of tumor progression or recurrence. Despite the improvement in cure rates, patients treated by radiotherapy are at risk of development of secondary malignancies. We conducted a comprehensive literature review of the secondary intracranial tumors that occurred following radiotherapy to pituitary adenomas to obtain clinicopathological characteristics. The analysis included 48 neuroepithelial tumors, 37 meningiomas, and 52 sarcomas which were published between 1959–2017, although data is missing regarding overall survival and type of irradiation in a significant proportion of the reports. The average onset age for the pituitary adenoma was 37.2 ± 14.4 years and the average latency period before the diagnosis of the secondary tumor was 15.2 ± 8.7 years. Radiotherapy was administered in pituitary adenomas at an average dose of 52.0 ± 19.5 Gy. The distribution of pituitary adenomas according to their function was prolactinoma in 10 (7.2%) cases, acromegaly in 37 (27.0%) cases, Cushing disease in 4 (2.9%) cases, PRL+GH in 1 (0.7%) case, non-functioning adenoma in 57 (41.6%) cases. Irradiation technique delivered was lateral opposing field in 23 (16.7%) cases, 3 or 4 field technique in 27 (19.6%) cases, rotation technique in 10 (7.2%) cases, radio surgery in 6 (4.3%) cases. Most of the glioma or sarcoma had been generated after lateral opposing field or 3/4 field technique. Fibrosarcomas were predominant before 1979 (p < 0.0001). The median overall survival time for all neuroepithelial tumors was 11 months (95% confidence intervals (CI), 3–14). Patients with gliomas treated with radiotherapy exhibited a non-significant positive trend with longer overall survival. The median overall survival time for sarcoma cases was 6 months (95% CI, 1.5–9). The median survival time in patients with radiation and/or chemotherapy for sarcomas exhibited a non-significant positive trend with longer overall survival. In patients treated with radiotherapy for pituitary adenomas, the risk of secondary tumor incidence warrants a longer follow up period. Moreover, radiation and/or chemotherapy should be considered in cases of secondary glioma or sarcoma following radiotherapy to the pituitary adenomas. Full article
(This article belongs to the Special Issue Radiation-Induced Carcinogenesis)
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1315 KiB  
Review
Significance of microRNAs in Androgen Signaling and Prostate Cancer Progression
by Ken-ichi Takayama, Aya Misawa and Satoshi Inoue
Cancers 2017, 9(8), 102; https://doi.org/10.3390/cancers9080102 - 07 Aug 2017
Cited by 32 | Viewed by 5917
Abstract
The androgen receptor (AR) plays important roles in prostate cancer development and prostate tumor growth. After binding to androgens, AR functions as a nuclear receptor and translocates to the nucleus to bind to specific AR-binding sites (ARBSs). AR regulates epigenetic factor recruitments to [...] Read more.
The androgen receptor (AR) plays important roles in prostate cancer development and prostate tumor growth. After binding to androgens, AR functions as a nuclear receptor and translocates to the nucleus to bind to specific AR-binding sites (ARBSs). AR regulates epigenetic factor recruitments to activate its downstream signaling. Although androgen deprivation therapy (ADT) is initially useful for prostate cancer patients, most patients eventually show resistance with hormone-refractory prostate cancers (HRPCs) or castration-resistant prostate cancers (CRPCs). Thus, new therapeutic strategies targeting HRPCs/CRPCs should be very important for clinical medicine as well as prostate cancer biology. Past studies have shown that mechanisms such as AR overexpression, hypersensitivity, variants and reprograming are responsible for developing HRPCs/CRPCs. These findings suggest that AR target genes will be major key factors. In this review article, we focus mainly on the androgen-regulated microRNAs (miRNAs) to summarize the contribution of miRNA-mediated pathways for prostate cancer progression. Full article
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1256 KiB  
Review
Epithelial-to-Mesenchymal Transition and MicroRNAs in Lung Cancer
by Antoine Legras, Nicolas Pécuchet, Sandrine Imbeaud, Karine Pallier, Audrey Didelot, Hélène Roussel, Laure Gibault, Elizabeth Fabre, Françoise Le Pimpec-Barthes, Pierre Laurent-Puig and Hélène Blons
Cancers 2017, 9(8), 101; https://doi.org/10.3390/cancers9080101 - 03 Aug 2017
Cited by 68 | Viewed by 7915
Abstract
Despite major advances, non-small cell lung cancer (NSCLC) remains the major cause of cancer-related death in developed countries. Metastasis and drug resistance are the main factors contributing to relapse and death. Epithelial-to-mesenchymal transition (EMT) is a complex molecular and cellular process involved in [...] Read more.
Despite major advances, non-small cell lung cancer (NSCLC) remains the major cause of cancer-related death in developed countries. Metastasis and drug resistance are the main factors contributing to relapse and death. Epithelial-to-mesenchymal transition (EMT) is a complex molecular and cellular process involved in tissue remodelling that was extensively studied as an actor of tumour progression, metastasis and drug resistance in many cancer types and in lung cancers. Here we described with an emphasis on NSCLC how the changes in signalling pathways, transcription factors expression or microRNAs that occur in cancer promote EMT. Understanding the biology of EMT will help to define reversing process and treatment strategies. We will see that this complex mechanism is related to inflammation, cell mobility and stem cell features and that it is a dynamic process. The existence of intermediate phenotypes and tumour heterogeneity may be debated in the literature concerning EMT markers, EMT signatures and clinical consequences in NSCLC. However, given the role of EMT in metastasis and in drug resistance the development of EMT inhibitors is an interesting approach to counteract tumour progression and drug resistance. This review describes EMT involvement in cancer with an emphasis on NSCLC and microRNA regulation. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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240 KiB  
Review
Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas
by Coralie Hoareau-Aveilla and Fabienne Meggetto
Cancers 2017, 9(8), 100; https://doi.org/10.3390/cancers9080100 - 03 Aug 2017
Cited by 23 | Viewed by 5093
Abstract
The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and [...] Read more.
The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin’s lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
681 KiB  
Article
Performance of a RT-PCR Assay in Comparison to FISH and Immunohistochemistry for the Detection of ALK in Non-Small Cell Lung Cancer
by David R. Hout, Brock L. Schweitzer, Kasey Lawrence, Stephan W. Morris, Tracy Tucker, Rosetta Mazzola, Rachel Skelton, Frank McMahon, John Handshoe, Mary Lesperance, Aly Karsan and David L. Saltman
Cancers 2017, 9(8), 99; https://doi.org/10.3390/cancers9080099 - 01 Aug 2017
Cited by 21 | Viewed by 6562
Abstract
Patients with lung cancers harboring an activating anaplastic lymphoma kinase (ALK) rearrangement respond favorably to ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are validated and widely used screening tests for ALK rearrangements but both methods have limitations. [...] Read more.
Patients with lung cancers harboring an activating anaplastic lymphoma kinase (ALK) rearrangement respond favorably to ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are validated and widely used screening tests for ALK rearrangements but both methods have limitations. The ALK RGQ RT-PCR Kit (RT-PCR) is a single tube quantitative real-time PCR assay for high throughput and automated interpretation of ALK expression. In this study, we performed a direct comparison of formalin-fixed paraffin-embedded (FFPE) lung cancer specimens using all three ALK detection methods. The RT-PCR test (diagnostic cut-off ΔCt of ≤8) was shown to be highly sensitive (100%) when compared to FISH and IHC. Sequencing of RNA detected full-length ALK transcripts or EML4-ALK and KIF5B-ALK fusion variants in discordant cases in which ALK expression was detected by the ALK RT-PCR test but negative by FISH and IHC. The overall specificity of the RT-PCR test for the detection of ALK in cases without full-length ALK expression was 94% in comparison to FISH and sequencing. These data support the ALK RT-PCR test as a highly efficient and reliable diagnostic screening approach to identify patients with non-small cell lung cancer whose tumors are driven by oncogenic ALK. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
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669 KiB  
Review
EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids
by Elvira Forte, Isotta Chimenti, Paolo Rosa, Francesco Angelini, Francesca Pagano, Antonella Calogero, Alessandro Giacomello and Elisa Messina
Cancers 2017, 9(8), 98; https://doi.org/10.3390/cancers9080098 - 29 Jul 2017
Cited by 60 | Viewed by 11183
Abstract
The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features [...] Read more.
The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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Commentary
Localization of VEGF to Vascular ECM Is an Important Aspect of Tumor Angiogenesis
by Weon-Kyoo You and William B. Stallcup
Cancers 2017, 9(8), 97; https://doi.org/10.3390/cancers9080097 - 28 Jul 2017
Cited by 8 | Viewed by 5715
Abstract
Our research has identified several examples in which reduced VEGF-A binding to deficient vascular extracellular matrix leads to deficits in tumor vascularization and tumor growth: (1) germline ablation of collagen VI in the stroma of intracranial B16F10 melanomas; (2) knockdown of the Tks5 [...] Read more.
Our research has identified several examples in which reduced VEGF-A binding to deficient vascular extracellular matrix leads to deficits in tumor vascularization and tumor growth: (1) germline ablation of collagen VI in the stroma of intracranial B16F10 melanomas; (2) knockdown of the Tks5 scaffolding protein in MDA-MB-231 mammary tumor cells; (3) germline ablation of NG2 proteoglycan in the stroma of MMTV-PyMT mammary tumors; and (4) myeloid-specific ablation of NG2 in the stroma of intracranial B16F10 melanomas. Tumor hypoxia is increased in each of the four types of experimental mice, accompanied by increases in total VEGF-A. However, while VEGF-A is highly associated with tumor blood vessels in control mice, it is much more diffusely distributed in tumors in all four sets of experimental mice, likely due to reduced extent of the vascular extracellular matrix. In parallel to lost VEGF-A localization, tumor vessels in each case have smaller diameters and are leakier than tumor vessels in control mice. Tumor growth is decreased as a result of this poor vascular function. The fact that the observed vascular changes occur in the absence of alterations in vascular density suggests that examination of vessel structure and function is more useful than vascular density for understanding the importance of angiogenesis in tumor progression. Full article
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Article
Involvement of the Integrin α1β1 in the Progression of Colorectal Cancer
by Salah Boudjadi, Gérald Bernatchez, Blanche Sénicourt, Marco Beauséjour, Pierre H. Vachon, Julie C. Carrier and Jean-François Beaulieu
Cancers 2017, 9(8), 96; https://doi.org/10.3390/cancers9080096 - 26 Jul 2017
Cited by 31 | Viewed by 5724
Abstract
Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role [...] Read more.
Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role in fibroblast proliferation. In the small intestine, the integrin α1 subunit is present in the crypt proliferative compartment and absent in the villus. We have recently shown that the integrin α1 protein and transcript (ITGA1) are present in a large proportion of colorectal cancers (CRC) and that their expression is controlled by the MYC oncogenic factor. Considering that α1 subunit/ITGA1 expression is correlated with MYC in more than 70% of colon adenocarcinomas, we postulated that the integrin α1β1 has a pro-tumoral contribution to CRC. In HT29, T84 and SW480 CRC cells, α1 subunit/ITGA1 knockdown resulted in a reduction of cell proliferation associated with an impaired resistance to anoikis and an altered cell migration in HT29 and T84 cells. Moreover, tumor development in xenografts was reduced in HT29 and T84 sh-ITGA1 cells, associated with extensive necrosis, a low mitotic index and a reduced number of blood vessels. Our results show that α1β1 is involved in tumor cell proliferation, survival and migration. This finding suggests that α1β1 contributes to CRC progression. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review
Integrins and Exosomes, a Dangerous Liaison in Cancer Progression
by Mayra Paolillo and Sergio Schinelli
Cancers 2017, 9(8), 95; https://doi.org/10.3390/cancers9080095 - 26 Jul 2017
Cited by 83 | Viewed by 6899
Abstract
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles [...] Read more.
Integrin activity and function is classically related to the bi-directional regulation of cell-extracellular matrix (ECM) contacts that regulate a number of cell pathways linked to cell adhesion, cell detachment from ECM, cell migration, and anoikis. Interestingly, emerging data continue to uncover new roles for integrins in cancer-relevant pathways, particularly concerning the regulation of immune cell activity in the tumor niche, like myeloid cell differentiation and function and, very recently, the regulation of metastatic processes by exosomes. Exosomes are deeply involved in cell-cell communication processes and several studies have shown that integrins found in tumor-associated exosomes can promote cancer progression by two novel cooperative mechanisms: horizontal transfer of integrin transcripts as vescicle cargo, and selection of target tissues to form new tumor niches during metastatic spread by integrins carried on the exosome’s surface. In this review we will discuss mounting evidence that contribute to the development of a new picture for integrins in cancer, highlighting the role of integrins in the processes that leads to tumor niche formation. In particular, the role of the periostin pathway in the recruitment of tumor-associated macrophages, and the proposed contribution of exosome-derived integrins in the metastatic spread will be discussed. Finally, in light of the above considerations, an evaluation of integrins as possible therapeutic targets will be conducted. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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