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Cancers, Volume 3, Issue 1 (March 2011) , Pages 1-1479

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Open AccessArticle
Overexpression of CYP3A4 in a COLO 205 Colon Cancer Stem Cell Model in vitro
Cancers 2011, 3(1), 1467-1479; https://doi.org/10.3390/cancers3011467
Received: 30 January 2011 / Revised: 9 February 2011 / Accepted: 9 February 2011 / Published: 22 March 2011
Cited by 6 | Viewed by 6366 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
Cancer stem cells (CSCs) seem to constitute a subpopulation of tumor cells that escape from chemotherapy and cause recurrent disease. Low proliferation rates, protection in a stem cell niche and overexpression of drug resistance proteins are considered to confer chemoresistance. We established an [...] Read more.
Cancer stem cells (CSCs) seem to constitute a subpopulation of tumor cells that escape from chemotherapy and cause recurrent disease. Low proliferation rates, protection in a stem cell niche and overexpression of drug resistance proteins are considered to confer chemoresistance. We established an in vitro colon CSC-like model using the COLO 205 cell line, which revealed transiently increased expression of CD133 when transferred to serum-free stem cell culture medium. Assessment of global gene expression of COLO 205 cells under these conditions identified a set of upregulated genes including cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase 1A1 (ALDH1A1), as confirmed by real-time qPCR. ALDH1A1 is a CSC marker for certain tumor entities and confers resistance to cyclophosphamide. CYP3A4 is expressed in liver and colon and its overexpression seems particularly relevant in colon cancer, since it inactivates irinotecan and other xenobiotics, such as taxols and vinca alkaloids. In conclusion, this COLO 205 model provides evidence for CD133 induction concomitant with overexpression of CYP3A4, which, together with ATP-binding cassette, subfamily G, member 2 (ABCG2) and others, may have a role in chemoresistant colon CSCs and a negative impact on disease-free survival in colon cancer patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessCase Report
Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report
Cancers 2011, 3(1), 1454-1466; https://doi.org/10.3390/cancers3011454
Received: 7 January 2011 / Accepted: 21 February 2011 / Published: 17 March 2011
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Abstract
The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression [...] Read more.
The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated. Full article
Open AccessReview
The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer
Cancers 2011, 3(1), 1426-1453; https://doi.org/10.3390/cancers3011426
Received: 29 December 2010 / Revised: 9 March 2011 / Accepted: 10 March 2011 / Published: 17 March 2011
Cited by 15 | Viewed by 6125 | PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, [...] Read more.
Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. Full article
(This article belongs to the Special Issue Lung Cancer)
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Open AccessReview
Breast Cancer-Initiating Cells: Insights into Novel Treatment Strategies
Cancers 2011, 3(1), 1405-1425; https://doi.org/10.3390/cancers3011405
Received: 14 January 2011 / Revised: 17 February 2011 / Accepted: 2 March 2011 / Published: 16 March 2011
Cited by 5 | Viewed by 5161 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24/low and/or CD133+ expression) or enzymatic activity [...] Read more.
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview
Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer
Cancers 2011, 3(1), 1383-1404; https://doi.org/10.3390/cancers3011383
Received: 30 January 2011 / Revised: 7 March 2011 / Accepted: 8 March 2011 / Published: 16 March 2011
Cited by 66 | Viewed by 7827 | PDF Full-text (563 KB) | HTML Full-text | XML Full-text
Abstract
Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone [...] Read more.
Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone demethylases. This family of enzymes contains a JmjC domain and is capable of removing tri- and di- methyl marks from lysine 4 on histone H3. Among these proteins, RBP2 mediates drug resistance while JARID1B is required for melanoma maintenance. Preclinical studies suggest inhibition of these enzymes can suppress tumorigenesis and provide strong rationale for development of their inhibitors for use in cancer therapy. Full article
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
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Open AccessReview
The Potential Use of N-Myristoyltransferase as a Biomarker in the Early Diagnosis of Colon Cancer
Cancers 2011, 3(1), 1372-1382; https://doi.org/10.3390/cancers3011372
Received: 6 February 2011 / Revised: 9 March 2011 / Accepted: 11 March 2011 / Published: 16 March 2011
Cited by 3 | Viewed by 5108 | PDF Full-text (511 KB) | HTML Full-text | XML Full-text
Abstract
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% [...] Read more.
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% of cancer patients when initially diagnosed. The majority of colon cancers develop from noncancerous adenomatous polyps on the lining of the colon which grow over the years to become cancerous. If detected early, the surgical resections of the growth, often in combination with chemotherapy, significantly increases life expectancy. We have shown that the enzyme N-myristoyltransferase (NMT) which carries out lipid modification of several proteins (including many of those involved in oncogenesis) is expressed at higher levels in cancerous tissues from the colon. We have also shown that in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells collected from colon cancer patients and from azoxymethane-induced rats the expression and localization of NMT is altered. We have observed strong positivity for NMT in immunohistochemical analysis for PBMC from colon cancer patients as compared to control groups. Furthermore, in the bone marrow (BM) mononuclear cells, NMT was found to be confined to the nuclei whereas in control groups it was observed to be located in the cytoplasm. In conclusion, this strikingly differential localization offers the basis of a potential investigational tool for screening or diagnosis of individuals at risk for or suspected of having colon cancer. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Open AccessReview
Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects
Cancers 2011, 3(1), 1351-1371; https://doi.org/10.3390/cancers3011351
Received: 14 January 2011 / Revised: 28 February 2011 / Accepted: 3 March 2011 / Published: 15 March 2011
Cited by 481 | Viewed by 18588 | PDF Full-text (329 KB) | HTML Full-text | XML Full-text
Abstract
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated [...] Read more.
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessArticle
The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis
Cancers 2011, 3(1), 1329-1350; https://doi.org/10.3390/cancers3011329
Received: 5 February 2011 / Revised: 15 February 2011 / Accepted: 10 March 2011 / Published: 15 March 2011
Cited by 8 | Viewed by 6782 | PDF Full-text (1399 KB) | HTML Full-text | XML Full-text
Abstract
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary [...] Read more.
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview
Cancer Stem Cells in Breast Cancer
Cancers 2011, 3(1), 1311-1328; https://doi.org/10.3390/cancers3011311
Received: 17 February 2011 / Revised: 3 March 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
Cited by 11 | Viewed by 9050 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
Abstract
The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells [...] Read more.
The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cells in their chemoresistance and their tumorigenic and metastatic activities. In this review, we focus on recent reports regarding the identification of CSC markers and the molecular mechanism of CSC phenotypes to understand the basic properties and molecular target of CSCs. In addition, we especially focus on the CSCs of breast cancer since the use of neoadjuvant chemotherapy can lead to the enrichment of CSCs in patients with that disease. The identification of CSC markers and an improved understanding of the molecular mechanism of CSC phenotypes should lead to progress in cancer therapy and improved prognoses for patients with cancer. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview
Glutathione in Cancer Cell Death
Cancers 2011, 3(1), 1285-1310; https://doi.org/10.3390/cancers3011285
Received: 30 December 2010 / Revised: 22 February 2011 / Accepted: 9 March 2011 / Published: 11 March 2011
Cited by 103 | Viewed by 9990 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one [...] Read more.
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessArticle
The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status
Cancers 2011, 3(1), 1274-1284; https://doi.org/10.3390/cancers3011274
Received: 19 January 2011 / Revised: 28 February 2011 / Accepted: 4 March 2011 / Published: 11 March 2011
Cited by 4 | Viewed by 5254 | PDF Full-text (238 KB) | HTML Full-text | XML Full-text
Abstract
The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of [...] Read more.
The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of 116 patients with UICC stage II and III sporadic colorectal cancer. The results were correlated with overall and recurrence-free survival. The mean observation period was 51.8 ± 2.5 months. Expression of p53 was observed in 72 tumors (63%). Overall survival was significantly better in patients with p53-positive carcinomas than in those without p53 expression (p = 0.048). No differences were found in recurrence-free survival (p = 0.161). The p53+/p21− combination was seen in 68% (n = 49), the p53+/p21+ combination in 32% (n = 23). Patients with p53+/p21− carcinomas had significantly better overall and recurrence-free survival than those with p53+/p21+ (p < 0.0001 resp. p = 0.003). Our data suggest that the prognostic impact of p53 expression on sporadic colorectal cancer is dependent on p21 status. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview
Current State of Surgical Management of Pancreatic Cancer
Cancers 2011, 3(1), 1253-1273; https://doi.org/10.3390/cancers3011253
Received: 10 February 2011 / Revised: 19 February 2011 / Accepted: 10 March 2011 / Published: 10 March 2011
Cited by 4 | Viewed by 5495 | PDF Full-text (444 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival [...] Read more.
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival rates to approximately 20–25%. Pancreatic surgery is a technically challenging procedure and has significantly changed during the past decades with regard to technical aspects as well as perioperative care. Standardized resections can be carried out with low morbidity and mortality below 5% in high volume institutions. Furthermore, there is growing evidence that also more extended resections including multivisceral approaches, vessel reconstructions or surgery for tumor recurrence can be carried out safely with favorable outcomes. The impact of adjuvant treatment, especially chemotherapy, has increased dramatically within recent years, leading to significantly improved postoperative survival, making pancreatic cancer therapy an interdisciplinary approach to achieve best results. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview
Cancer Stem Cell Radioresistance and Enrichment: Where Frontline Radiation Therapy May Fail in Lung and Esophageal Cancers
Cancers 2011, 3(1), 1232-1252; https://doi.org/10.3390/cancers3011232
Received: 7 December 2010 / Revised: 25 January 2011 / Accepted: 24 February 2011 / Published: 10 March 2011
Cited by 36 | Viewed by 7308 | PDF Full-text (1331 KB) | HTML Full-text | XML Full-text
Abstract
Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient prognosis. [...] Read more.
Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient prognosis. In reviewing this new area of cancer biology, we will give an overview of the current literature regarding lung and esophageal CSCs and radioresistance of CSC, and discuss the potential therapeutic applications of these findings. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview
Analysis of Somatic Mutations in Cancer: Molecular Mechanisms of Activation in the ErbB Family of Receptor Tyrosine Kinases
Cancers 2011, 3(1), 1195-1231; https://doi.org/10.3390/cancers3011195
Received: 7 January 2011 / Revised: 28 February 2011 / Accepted: 1 March 2011 / Published: 10 March 2011
Cited by 9 | Viewed by 5398 | PDF Full-text (871 KB) | HTML Full-text | XML Full-text
Abstract
The ErbB/EGFR/HER family of kinases consists of four homologous receptor tyrosine kinases which are important regulatory elements in many cellular processes, including cell proliferation, differentiation, and migration. Somatic mutations in, or over-expression of, the ErbB family is found in many cancers and is [...] Read more.
The ErbB/EGFR/HER family of kinases consists of four homologous receptor tyrosine kinases which are important regulatory elements in many cellular processes, including cell proliferation, differentiation, and migration. Somatic mutations in, or over-expression of, the ErbB family is found in many cancers and is correlated with a poor prognosis; particularly, clinically identified mutations found in non-small-cell lung cancer (NSCLC) of ErbB1 have been shown to increase its basal kinase activity and patients carrying these mutations respond remarkably to the small tyrosine kinase inhibitor gefitinib. Here, we analyze the potential effects of the currently catalogued clinically identified mutations in the ErbB family kinase domains on the molecular mechanisms of kinase activation. Recently, we identified conserved networks of hydrophilic and hydrophobic interactions characteristic to the active and inactive conformation, respectively. Here, we show that the clinically identified mutants influence the kinase activity in distinctive fashion by affecting the characteristic interaction networks. Full article
(This article belongs to the Special Issue Lung Cancer)
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Open AccessReview
Cardiac Hormones Target the Ras-MEK 1/2-ERK 1/2 Kinase Cancer Signaling Pathways
Cancers 2011, 3(1), 1182-1194; https://doi.org/10.3390/cancers3011182
Received: 18 February 2011 / Revised: 2 March 2011 / Accepted: 3 March 2011 / Published: 8 March 2011
Cited by 2 | Viewed by 7068 | PDF Full-text (340 KB) | HTML Full-text | XML Full-text
Abstract
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney [...] Read more.
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor’s ability to stimulate ERK and Ras. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunocytochemical studies to inhibit DNA synthesis within cancer cells. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Open AccessReview
Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential
Cancers 2011, 3(1), 1158-1181; https://doi.org/10.3390/cancers3011158
Received: 30 January 2011 / Accepted: 23 February 2011 / Published: 7 March 2011
Cited by 13 | Viewed by 5541 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text
Abstract
Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, [...] Read more.
Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview
Retrotransposon-Encoded Reverse Transcriptase in the Genesis, Progression and Cellular Plasticity of Human Cancer
Cancers 2011, 3(1), 1141-1157; https://doi.org/10.3390/cancers3011141
Received: 11 January 2011 / Revised: 21 February 2011 / Accepted: 22 February 2011 / Published: 7 March 2011
Cited by 12 | Viewed by 5963 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, are [...] Read more.
LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, are generally expressed at low levels in differentiated cells, but their expression is upregulated in transformed cells and embryonic tissues. Here we discuss a recently discovered RT-dependent mechanism that operates in tumorigenesis and reversibly modulates phenotypic and functional variations associated with tumor progression. Downregulation of active LINE-1 elements drastically reduces the tumorigenic potential of cancer cells, paralleled by reduced proliferation and increased differentiation. Pharmacological RT inhibitors (e.g., nevirapine and efavirenz) exert similar effects on tumorigenic cell lines, both in culture and in animal models. The HERV-K family play a distinct complementary role in stress-dependent transition of melanoma cells from an adherent, non-aggressive, to a non-adherent, highly malignant, growth phenotype. In synthesis, the retrotransposon-encoded RT is increasingly emerging as a key regulator of tumor progression and a promising target in a novel anti-cancer therapy. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview
Genetic Alterations in Glioma
Cancers 2011, 3(1), 1129-1140; https://doi.org/10.3390/cancers3011129
Received: 4 January 2011 / Revised: 28 February 2011 / Accepted: 1 March 2011 / Published: 7 March 2011
Cited by 9 | Viewed by 4776 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth [...] Read more.
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
Drug Treatment of Cancer Cell Lines: A Way to Select for Cancer Stem Cells?
Cancers 2011, 3(1), 1111-1128; https://doi.org/10.3390/cancers3011111
Received: 4 January 2011 / Revised: 31 January 2011 / Accepted: 24 February 2011 / Published: 4 March 2011
Cited by 4 | Viewed by 5325 | PDF Full-text (138 KB) | HTML Full-text | XML Full-text
Abstract
Tumors are generally composed of different cell types. In recent years, it has been shown that in many types of cancers a subset of cells show peculiar characteristics, such as the ability to induce tumors when engrafted into host animals, self-renew and being [...] Read more.
Tumors are generally composed of different cell types. In recent years, it has been shown that in many types of cancers a subset of cells show peculiar characteristics, such as the ability to induce tumors when engrafted into host animals, self-renew and being immortal, and give rise to a differentiated progeny. These cells have been defined as cancer stem cells (CSCs) or tumor initiating cells. CSCs can be isolated both from tumor specimens and established cancer cell lines on the basis of their ability to exclude fluorescent dyes, express specific cell surface markers or grow in particular culture conditions. A key feature of CSCs is their resistance to chemotherapeutic agents, which could contribute to the remaining of residual cancer cells after therapeutic treatments. It has been shown that CSC-like cells can be isolated after drug treatment of cancer cell lines; in this review, we will describe the strategies so far applied to identify and isolate CSCs. Furthermore, we will discuss the possible use of these selected populations to investigate CSC biology and develop new anticancer drugs. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview
Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics
Cancers 2011, 3(1), 1081-1110; https://doi.org/10.3390/cancers3011081
Received: 17 December 2010 / Revised: 19 January 2011 / Accepted: 21 January 2011 / Published: 4 March 2011
Cited by 72 | Viewed by 8078 | PDF Full-text (1890 KB) | HTML Full-text | XML Full-text
Abstract
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical [...] Read more.
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessReview
Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies
Cancers 2011, 3(1), 1042-1080; https://doi.org/10.3390/cancers3011042
Received: 8 January 2011 / Revised: 18 February 2011 / Accepted: 1 March 2011 / Published: 3 March 2011
Cited by 7 | Viewed by 7404 | PDF Full-text (6230 KB) | HTML Full-text | XML Full-text
Abstract
Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, [...] Read more.
Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview
Targets and Mechanisms of Photodynamic Therapy in Lung Cancer Cells: A Brief Overview
Cancers 2011, 3(1), 1014-1041; https://doi.org/10.3390/cancers3011014
Received: 31 December 2010 / Revised: 20 February 2011 / Accepted: 1 March 2011 / Published: 3 March 2011
Cited by 31 | Viewed by 4880 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer remains one of the most common cancer-related causes of death. This type of cancer typically develops over a period of many years, and if detected at an early enough stage can be eliminated by a variety of treatments including photodynamic therapy [...] Read more.
Lung cancer remains one of the most common cancer-related causes of death. This type of cancer typically develops over a period of many years, and if detected at an early enough stage can be eliminated by a variety of treatments including photodynamic therapy (PDT). A critical discussion on the clinical applications of PDT in lung cancer is well outside the scope of the present report, which, in turn focuses on mechanistic and other aspects of the photodynamic action at a molecular and cellular level. The knowledge of these issues at pre-clinical levels is necessary to develop, check and adopt appropriate clinical protocols in the future. This report, besides providing general information, includes a brief overview of present experimental PDT and provides some non-exhaustive information on current strategies aimed at further improving the efficacy, especially in regard to lung cancer cells. Full article
(This article belongs to the Special Issue Lung Cancer)
Open AccessReview
Role of p53 in Cell Death and Human Cancers
Cancers 2011, 3(1), 994-1013; https://doi.org/10.3390/cancers3010994
Received: 7 December 2010 / Revised: 22 February 2011 / Accepted: 22 February 2011 / Published: 3 March 2011
Cited by 70 | Viewed by 10768 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative [...] Read more.
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview
Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer
Cancers 2011, 3(1), 982-993; https://doi.org/10.3390/cancers3010982
Received: 15 December 2010 / Revised: 22 February 2011 / Accepted: 24 February 2011 / Published: 3 March 2011
Cited by 7 | Viewed by 5640 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, [...] Read more.
Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression. Full article
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
Open AccessReview
Muscarinic Receptor Signaling in Colon Cancer
Cancers 2011, 3(1), 971-981; https://doi.org/10.3390/cancers3010971
Received: 31 January 2011 / Revised: 14 February 2011 / Accepted: 24 February 2011 / Published: 2 March 2011
Cited by 13 | Viewed by 6254 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
Abstract
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal [...] Read more.
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
Open AccessReview
An Evolutionary Explanation for the Perturbation of the Dynamics of Metastatic Tumors Induced by Surgery and Acute Inflammation
Cancers 2011, 3(1), 945-970; https://doi.org/10.3390/cancers3010945
Received: 4 January 2011 / Revised: 17 February 2011 / Accepted: 22 February 2011 / Published: 2 March 2011
Cited by 1 | Viewed by 4857 | PDF Full-text (776 KB) | HTML Full-text | XML Full-text
Abstract
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as [...] Read more.
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as follows: (1) the resection of the primary tumor is able to accelerate the evolution of micrometastasis in early stages, and (2) the outcome is transiently opposed in advanced tumors. The objective of this paper is to give some insight into tumorigenesis and surgery-related effects, by applying the concepts of the evolutionary theory in those tumor behaviors that gompertzian and tissular-centered models are unable to explain. According to this view, tumors are the consequence of natural selection operating at the somatic level, which is the basic mechanism of tumorigenesis, notwithstanding the complementary role of the intrinsic constrictions of complex networks. A tumor is a complicated phenomenon that entails growth, evolution and development simultaneously. So, an evo-devo perspective can explain how and why tumor subclones are able to translate competition from a metabolic level into neoangiogenesis and the immune response. The paper proposes that distant interactions are an extension of the ecological events at the local level. This notion explains the evolutionary basis for tumor dormancy, and warns against the teleological view of tumorigenesis as a process directed towards the maximization of a concrete trait such as aggressiveness. Full article
Open AccessReview
Inflammation and Tumor Microenvironment in Lymph Node Metastasis
Cancers 2011, 3(1), 927-944; https://doi.org/10.3390/cancers3010927
Received: 11 January 2011 / Revised: 17 February 2011 / Accepted: 21 February 2011 / Published: 1 March 2011
Cited by 7 | Viewed by 5875 | PDF Full-text (937 KB) | HTML Full-text | XML Full-text
Abstract
In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are mechanistically [...] Read more.
In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are mechanistically involved in LN metastasis. We highlight recent data that link tumor microenvironment, including inflammation (at the cellular and cytokine levels) and tumor-induced lymphangiogenesis, with nodal metastasis. Many of the newly identified genes that appear to influence LN metastasis facilitate general motility, chemotactic, or invasive properties that also increase the ability of cancer cells to disseminate and survive at distant organ sites. These new biomarkers will help predict clinical outcome and point to novel future therapies in metastatic melanoma as well as other cancers. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview
Protein Kinase A in Cancer
Cancers 2011, 3(1), 913-926; https://doi.org/10.3390/cancers3010913
Received: 17 January 2011 / Revised: 9 February 2011 / Accepted: 22 February 2011 / Published: 28 February 2011
Cited by 28 | Viewed by 5543 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in [...] Read more.
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in signal transduction have been extensively studied, for example oncogenes, while modifications in intracellular compartmentalization of these molecules, or changes in the expression of unmodified genes have received less attention. Yet, epigenetic modulation of second messenger systems can deeply modify cellular functioning and in the end may cause instability of many processes, including cell mitosis. It is important to understand the functional meaning of modifications in second messenger intracellular pathways and unravel the role of downstream proteins in the initiation and growth of tumors. Within this framework, the cAMP system has been examined. cAMP is a second messenger involved in regulation of a variety of cellular functions. It acts mainly through its binding to cAMP-activated protein kinases (PKA), that were suggested to participate in the onset and progression of various tumors. PKA may represent a biomarker for tumor detection, identification and staging, and may be a potential target for pharmacological treatment of tumors. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer
Cancers 2011, 3(1), 897-912; https://doi.org/10.3390/cancers3010897
Received: 13 January 2011 / Revised: 1 February 2011 / Accepted: 14 February 2011 / Published: 25 February 2011
Cited by 8 | Viewed by 6833 | PDF Full-text (428 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is [...] Read more.
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview
Components of Cell-Matrix Linkage as Potential New Markers for Prostate Cancer
Cancers 2011, 3(1), 883-896; https://doi.org/10.3390/cancers3010883
Received: 25 January 2011 / Revised: 12 February 2011 / Accepted: 17 February 2011 / Published: 25 February 2011
Cited by 4 | Viewed by 5042 | PDF Full-text (344 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is one of the most common tumor diseases worldwide. Often being non-aggressive, prostate tumors in these cases do not need immediate treatment. However, about 20% of diagnosed prostate cancers tend to metastasize and require treatment. Existing diagnostic methods may fail to [...] Read more.
Prostate cancer is one of the most common tumor diseases worldwide. Often being non-aggressive, prostate tumors in these cases do not need immediate treatment. However, about 20% of diagnosed prostate cancers tend to metastasize and require treatment. Existing diagnostic methods may fail to accurately recognize the transition of a dormant, non-aggressive tumor into highly malignant prostate cancer. Therefore, new diagnostic tools are needed to improve diagnosis and therapy of prostate carcinoma. This review evaluates existing methods to diagnose prostate carcinoma, such as the biochemical marker prostate-specific antigen (PSA), but also discusses the possibility to use the altered expression of integrins and laminin-332 in prostate carcinomas as diagnostic tools and therapeutic targets of prostate cancer. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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