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BBA - Reviews on Cancer (v.1816, #2)
Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets?
by Ashraf A. Khalil; Nihal F. Kabapy; Sahar F. Deraz; Christopher Smith (pp. 89-104).
Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer.
Keywords: Abbreviations; 2 DE; 2D gel electrophoresis; 2DPAGE; 2D polyacrylamide gel electrophoresis; AIF; Apoptosis inducing factor; Apaf-1; Apoptotic protease activating factor 1; APC; Antigen presenting cell; ASK-1; Apoptosis Signal-regulating Kinase 1; Bag; Bcl-2-associated athanogene; BAX; Bcl-2-associated X protein; CAD; Caspase activated DNase; CARD; Caspase-recruitment domain; CCT; Cytosolic chaperonin; COPD; Chronic obstructive pulmonary disease; CRC; Colorectal carcinoma; DAXX; Death Associated Protein 6; DFF 40; DNA fragmentation factor 40; DISC; Death Inducing Signalling Complex; ds; double-stranded; EGFR; Endothelial growth factor receptor; ELISA; Enzyme linked immuno-sorbent assay; ER; Estrogen receptor; FADD; Fas Associated Death Domain; GP; Glycoprotein; GRP; Glucose regulated protein; HCC; Hepatocellular carcinoma; Her; Human epidermal growth factor receptor; Hip; HSC70 interacting protein; Hop; HSP organizing protein; HSC; Heat shock cognate; HSF; Heat shock transcription factor; HSP; Heat shock protein; ICAD; Inhibitor of caspase activated DNase; JNK; c-Jun N-terminal kinases; MAPK; Mitogen-activated protein kinase; MAPKAP; Mitogen-activated protein kinase-activated protein; MS; Mass spectrometry; MyoD; Myogenic differentiation protein; NFAT; Nuclear factor of activated T-cells; NF-KB; Nuclear factor- kappaB; NSCLC; Non small cell lung carcinoma; PET; Positron emission tomography; PKA; Protein kinase A; PKR; Protein kinase R; PP5; Protein phosphatase 5; ROS; Reactive oxygen species; SILAC; Stable isotope labelling with amino acids in cell culture; TRADD; TNF Receptor Associated Death Domain; TRAP1; Tumour necrosis factor type 1 receptor-associated protein1
Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets?
by Ashraf A. Khalil; Nihal F. Kabapy; Sahar F. Deraz; Christopher Smith (pp. 89-104).
Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer.
Keywords: Abbreviations; 2 DE; 2D gel electrophoresis; 2DPAGE; 2D polyacrylamide gel electrophoresis; AIF; Apoptosis inducing factor; Apaf-1; Apoptotic protease activating factor 1; APC; Antigen presenting cell; ASK-1; Apoptosis Signal-regulating Kinase 1; Bag; Bcl-2-associated athanogene; BAX; Bcl-2-associated X protein; CAD; Caspase activated DNase; CARD; Caspase-recruitment domain; CCT; Cytosolic chaperonin; COPD; Chronic obstructive pulmonary disease; CRC; Colorectal carcinoma; DAXX; Death Associated Protein 6; DFF 40; DNA fragmentation factor 40; DISC; Death Inducing Signalling Complex; ds; double-stranded; EGFR; Endothelial growth factor receptor; ELISA; Enzyme linked immuno-sorbent assay; ER; Estrogen receptor; FADD; Fas Associated Death Domain; GP; Glycoprotein; GRP; Glucose regulated protein; HCC; Hepatocellular carcinoma; Her; Human epidermal growth factor receptor; Hip; HSC70 interacting protein; Hop; HSP organizing protein; HSC; Heat shock cognate; HSF; Heat shock transcription factor; HSP; Heat shock protein; ICAD; Inhibitor of caspase activated DNase; JNK; c-Jun N-terminal kinases; MAPK; Mitogen-activated protein kinase; MAPKAP; Mitogen-activated protein kinase-activated protein; MS; Mass spectrometry; MyoD; Myogenic differentiation protein; NFAT; Nuclear factor of activated T-cells; NF-KB; Nuclear factor- kappaB; NSCLC; Non small cell lung carcinoma; PET; Positron emission tomography; PKA; Protein kinase A; PKR; Protein kinase R; PP5; Protein phosphatase 5; ROS; Reactive oxygen species; SILAC; Stable isotope labelling with amino acids in cell culture; TRADD; TNF Receptor Associated Death Domain; TRAP1; Tumour necrosis factor type 1 receptor-associated protein1
The neuronal influence on tumor progression
by Mario Mancino; Elisabet Ametller; Gascon Pedro Gascón; Vanessa Almendro (pp. 105-118).
Nerve fibers accompany blood and lymphatic vessels all over the body. An extensive amount of knowledge has been obtained with regard to tumor angiogenesis and tumor lymphangiogenesis, yet little is known about the potential biological effects of “neoneurogenesis”. Cancer cells can exploit the advantage of the factors released by the nerve fibers to generate a positive microenvironment for cell survival and proliferation. At the same time, they can stimulate the formation of neurites by secreting neurotrophic factors and axon guidance molecules. The neuronal influence on the biology of a neoplasm was initially described several decades ago. Since then, an increasing amount of experimental evidence strongly suggests the existence of reciprocal interactions between cancer cells and nerves in humans. Moreover, researchers have been able to demonstrate a crosstalk between cancer cells and nerve fibers as a strategy for survival. Despite all these evidence, a lot remains to be done in order to clarify the role of neurotransmitters, neuropeptides, and their associated receptor-initiated signaling pathways in the development and progression of cancer, and response to therapy. A global-wide characterization of the neurotransmitters or neuropeptides present in the tumor microenvironment would provide insights into the real biological influences of the neuronal tissue on tumor progression. This review is intended to discuss our current understanding of neurosignaling in cancer and its potential implications on cancer prevention and therapy. The review will focus on the soluble factors released by cancer cells and nerve endings, their biological effects and their potential relevance in the treatment of cancer.
Keywords: Neoneurogenesis; Neurotransmitters; Neuropeptides; Axon guidance molecules; Neurotrophic factors; Cancer progression; Perineural invasion
The neuronal influence on tumor progression
by Mario Mancino; Elisabet Ametller; Gascon Pedro Gascón; Vanessa Almendro (pp. 105-118).
Nerve fibers accompany blood and lymphatic vessels all over the body. An extensive amount of knowledge has been obtained with regard to tumor angiogenesis and tumor lymphangiogenesis, yet little is known about the potential biological effects of “neoneurogenesis”. Cancer cells can exploit the advantage of the factors released by the nerve fibers to generate a positive microenvironment for cell survival and proliferation. At the same time, they can stimulate the formation of neurites by secreting neurotrophic factors and axon guidance molecules. The neuronal influence on the biology of a neoplasm was initially described several decades ago. Since then, an increasing amount of experimental evidence strongly suggests the existence of reciprocal interactions between cancer cells and nerves in humans. Moreover, researchers have been able to demonstrate a crosstalk between cancer cells and nerve fibers as a strategy for survival. Despite all these evidence, a lot remains to be done in order to clarify the role of neurotransmitters, neuropeptides, and their associated receptor-initiated signaling pathways in the development and progression of cancer, and response to therapy. A global-wide characterization of the neurotransmitters or neuropeptides present in the tumor microenvironment would provide insights into the real biological influences of the neuronal tissue on tumor progression. This review is intended to discuss our current understanding of neurosignaling in cancer and its potential implications on cancer prevention and therapy. The review will focus on the soluble factors released by cancer cells and nerve endings, their biological effects and their potential relevance in the treatment of cancer.
Keywords: Neoneurogenesis; Neurotransmitters; Neuropeptides; Axon guidance molecules; Neurotrophic factors; Cancer progression; Perineural invasion
The multiple roles of amphiregulin in human cancer
by Benoit Busser; Lucie Sancey; Elisabeth Brambilla; Jean-Luc Coll; Amandine Hurbin (pp. 119-131).
Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor (EGFR). AREG plays a central role in mammary gland development and branching morphogenesis in organs and is expressed both in physiological and in cancerous tissues. Various studies have highlighted the functional role of AREG in several aspects of tumorigenesis, including self-sufficiency in generating growth signals, limitless replicative potential, tissue invasion and metastasis, angiogenesis, and resistance to apoptosis. The oncogenic activity of AREG has already been described in the most common human epithelial malignancies, such as lung, breast, colorectal, ovary and prostate carcinomas, as well as in some hematological and mesenchymal cancers. Furthermore, AREG is also involved in resistance to several cancer treatments.In this review, we describe the various roles of AREG in oncogenesis and discuss its translational potential, such as the development of anti-AREG treatments, based on AREG activity. In the last decade, independent groups have reported successful but sometimes contradictory results in relation to the potential of AREG to serve as a prognostic and/or predictive marker for oncology, especially with regard to anti-EGFR therapies. Thus, we also discuss the potential usefulness of using AREG as a therapeutic target and validated biomarker for predicting cancer outcomes or treatment efficacy.
Keywords: Abbreviations; AREG; amphiregulin; TACE; tumor-necrosis factor-alpha converting enzyme; ADAM; a disintegrin and metalloproteinase; CTF; carboxy-terminal fragment; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; EGFR-TKI; epidermal growth factor receptor tyrosine kinase inhibitor; TGF-α; tumor growth factor-alpha; HB-EGF; heparin-binding EGF-like growth factor; EREG; epiregulin; BTC; betacellulin; NRG; neuregulins; HER; human epidermoid receptors; MAPK; mitogen-activated protein kinase; PI3K; phosphoinositide 3-kinase; PLC; phospholipase C; SH2; Src homology domain 2; SOS; son of sevenless; MEK; mitogen-activated protein kinase kinase; ERK; extracellular signal-regulated kinases; mTOR; mammalian Target of Rapamycin; PKC; protein kinase C; GPCR; G-protein coupled receptor; TNF-α; tumor necrosis factor-alpha; KO; knock-out; IGF1; insulin like growth factor 1; BM–MSC; bone marrow–mesenchymal stem cells; LIF; leukemia-inhibitory factor; PHD2; prolyl-4-hydroxylase domain enzyme 2; HNSCC; head and neck squamous cell carcinoma; NSCLC; non small cell lung carcinoma; EMT; epithelial–mesenchymal transition; HIF; hypoxia-inducible transcription factor; VEGF; vascular endothelial growth factor; ECM; extracellular matrix; MMP; matrix metalloproteinase; SiRNAs; small interfering RNAsAmphiregulin; Cancer; Biomarker; Epidermal growth factor receptor tyrosine kinase inhibitor; Angiogenesis; Metastasis
The multiple roles of amphiregulin in human cancer
by Benoit Busser; Lucie Sancey; Elisabeth Brambilla; Jean-Luc Coll; Amandine Hurbin (pp. 119-131).
Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor (EGFR). AREG plays a central role in mammary gland development and branching morphogenesis in organs and is expressed both in physiological and in cancerous tissues. Various studies have highlighted the functional role of AREG in several aspects of tumorigenesis, including self-sufficiency in generating growth signals, limitless replicative potential, tissue invasion and metastasis, angiogenesis, and resistance to apoptosis. The oncogenic activity of AREG has already been described in the most common human epithelial malignancies, such as lung, breast, colorectal, ovary and prostate carcinomas, as well as in some hematological and mesenchymal cancers. Furthermore, AREG is also involved in resistance to several cancer treatments.In this review, we describe the various roles of AREG in oncogenesis and discuss its translational potential, such as the development of anti-AREG treatments, based on AREG activity. In the last decade, independent groups have reported successful but sometimes contradictory results in relation to the potential of AREG to serve as a prognostic and/or predictive marker for oncology, especially with regard to anti-EGFR therapies. Thus, we also discuss the potential usefulness of using AREG as a therapeutic target and validated biomarker for predicting cancer outcomes or treatment efficacy.
Keywords: Abbreviations; AREG; amphiregulin; TACE; tumor-necrosis factor-alpha converting enzyme; ADAM; a disintegrin and metalloproteinase; CTF; carboxy-terminal fragment; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; EGFR-TKI; epidermal growth factor receptor tyrosine kinase inhibitor; TGF-α; tumor growth factor-alpha; HB-EGF; heparin-binding EGF-like growth factor; EREG; epiregulin; BTC; betacellulin; NRG; neuregulins; HER; human epidermoid receptors; MAPK; mitogen-activated protein kinase; PI3K; phosphoinositide 3-kinase; PLC; phospholipase C; SH2; Src homology domain 2; SOS; son of sevenless; MEK; mitogen-activated protein kinase kinase; ERK; extracellular signal-regulated kinases; mTOR; mammalian Target of Rapamycin; PKC; protein kinase C; GPCR; G-protein coupled receptor; TNF-α; tumor necrosis factor-alpha; KO; knock-out; IGF1; insulin like growth factor 1; BM–MSC; bone marrow–mesenchymal stem cells; LIF; leukemia-inhibitory factor; PHD2; prolyl-4-hydroxylase domain enzyme 2; HNSCC; head and neck squamous cell carcinoma; NSCLC; non small cell lung carcinoma; EMT; epithelial–mesenchymal transition; HIF; hypoxia-inducible transcription factor; VEGF; vascular endothelial growth factor; ECM; extracellular matrix; MMP; matrix metalloproteinase; SiRNAs; small interfering RNAsAmphiregulin; Cancer; Biomarker; Epidermal growth factor receptor tyrosine kinase inhibitor; Angiogenesis; Metastasis
Genetic susceptibility to sporadic ovarian cancer: A systematic review
by M.G.M. Braem; L.J. Schouten; P.H.M. Peeters; P.A. van den Brandt; N.C. Onland-Moret (pp. 132-146).
Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations.A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP).The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway.Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene–gene and gene–environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.
Keywords: Ovarian cancer; Genetic susceptibility; Genetic variants; Risk assessment; Review; Polymorphism
Genetic susceptibility to sporadic ovarian cancer: A systematic review
by M.G.M. Braem; L.J. Schouten; P.H.M. Peeters; P.A. van den Brandt; N.C. Onland-Moret (pp. 132-146).
Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations.A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP).The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway.Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene–gene and gene–environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.
Keywords: Ovarian cancer; Genetic susceptibility; Genetic variants; Risk assessment; Review; Polymorphism
Ubiquitin-independent proteasomal degradation during oncogenic viral infections
by Jiwon Hwang; Laura Winkler; Robert F. Kalejta (pp. 147-157).
Most eukaryotic proteins destined for imminent destruction are first tagged with a chain of ubiquitin molecules and are subsequently dismantled by the proteasome. Ubiquitin-independent degradation of substrates by the proteasome, however, also occurs. The number of documented proteasome-dependent, ubiquitin-independent degradation events remains relatively small but continues to grow. Proteins involved in oncogenesis and tumor suppression make up the majority of the known cases for this type of protein destruction. Provocatively, viruses with confirmed or suspected oncogenic properties are also prominent participants in the pantheon of ubiquitin-independent proteasomal degradation events. In this review, we identify and describe examples of proteasome-dependent, ubiquitin-independent protein degradation that occur during tumor virus infections, speculate why this type of protein destruction may be preferred during oncogenesis, and argue that this uncommon type of protein turnover represents a prime target for antiviral and anticancer therapeutics.
Keywords: Ubiquitin-independent; Proteasome; Oncogenic viruses
Ubiquitin-independent proteasomal degradation during oncogenic viral infections
by Jiwon Hwang; Laura Winkler; Robert F. Kalejta (pp. 147-157).
Most eukaryotic proteins destined for imminent destruction are first tagged with a chain of ubiquitin molecules and are subsequently dismantled by the proteasome. Ubiquitin-independent degradation of substrates by the proteasome, however, also occurs. The number of documented proteasome-dependent, ubiquitin-independent degradation events remains relatively small but continues to grow. Proteins involved in oncogenesis and tumor suppression make up the majority of the known cases for this type of protein destruction. Provocatively, viruses with confirmed or suspected oncogenic properties are also prominent participants in the pantheon of ubiquitin-independent proteasomal degradation events. In this review, we identify and describe examples of proteasome-dependent, ubiquitin-independent protein degradation that occur during tumor virus infections, speculate why this type of protein destruction may be preferred during oncogenesis, and argue that this uncommon type of protein turnover represents a prime target for antiviral and anticancer therapeutics.
Keywords: Ubiquitin-independent; Proteasome; Oncogenic viruses
Cancers and the NSD family of histone lysine methyltransferases
by Masayo Morishita; Eric di Luccio (pp. 158-163).
Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic therapy of cancers is emerging as an effective and valuable approach to both the chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), Histone deacetylatase, and DNA methyltransferase, are emerging as key therapeutic targets.The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in chromatin integrity as evidenced by a growing number of conditions linked to the alterations and/or amplification of NSD1, NSD2, and/or NSD3. NSD1, NSD2 and NSD3 are associated with multiple cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early carcinogenesis events. In most cases, reducing the levels of NSD proteins would suppress cancer growth. NSD1 and NSD2 were isolated as genes linked to developmental diseases, such as Sotos syndrome and Wolf–Hirschhorn syndrome, respectively, implying versatile aspects of the NSD proteins. The NSD pathways, however, are not well understood. It is noteworthy that the NSD family is phylogenetically distinct compared to other known lysine-HMTases, Here, we review the current knowledge on NSD1/NSD2/NSD3 in tumorigenesis and prospect their special value for developing novel anticancer drugs.
Keywords: Abbreviations; NSD; nuclear receptor binding SET domain; HMTase; Histone Methyl Transferase; AdoMet; S-Adenosylmethionine; AdoHcy; S-AdenosylhomocysteineTranscription factor; Histone lysine methyl transferase; NSD1; NSD2/MMSET/WHSC1; NSD3/WHSC1L1; Epigenetic cancer therapy
Cancers and the NSD family of histone lysine methyltransferases
by Masayo Morishita; Eric di Luccio (pp. 158-163).
Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic therapy of cancers is emerging as an effective and valuable approach to both the chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), Histone deacetylatase, and DNA methyltransferase, are emerging as key therapeutic targets.The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in chromatin integrity as evidenced by a growing number of conditions linked to the alterations and/or amplification of NSD1, NSD2, and/or NSD3. NSD1, NSD2 and NSD3 are associated with multiple cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early carcinogenesis events. In most cases, reducing the levels of NSD proteins would suppress cancer growth. NSD1 and NSD2 were isolated as genes linked to developmental diseases, such as Sotos syndrome and Wolf–Hirschhorn syndrome, respectively, implying versatile aspects of the NSD proteins. The NSD pathways, however, are not well understood. It is noteworthy that the NSD family is phylogenetically distinct compared to other known lysine-HMTases, Here, we review the current knowledge on NSD1/NSD2/NSD3 in tumorigenesis and prospect their special value for developing novel anticancer drugs.
Keywords: Abbreviations; NSD; nuclear receptor binding SET domain; HMTase; Histone Methyl Transferase; AdoMet; S-Adenosylmethionine; AdoHcy; S-AdenosylhomocysteineTranscription factor; Histone lysine methyl transferase; NSD1; NSD2/MMSET/WHSC1; NSD3/WHSC1L1; Epigenetic cancer therapy
New insights into mechanisms of resistance to microtubule inhibitors
by Anutosh Ganguly; Fernando Cabral (pp. 164-171).
Mechanisms to explain tumor cell resistance to drugs that target the microtubule cytoskeleton have relied on the assumption that the drugs act either to suppress microtubule dynamics or to perturb the balance between assembled and nonassembled tubulin. Recently, however, it was found that these drugs also alter the stability of microtubule attachment to centrosomes, and do so at the same concentrations that are needed to inhibit cell division. Based on this new information, a new model is presented that explains resistance resulting from a variety of molecular changes that have been reported in the literature. The improved understanding of drug action and resistance has important implications for chemotherapy with these agents.
Keywords: Abbreviations; CHO; Chinese hamster ovary; Cmd; colcemid; MAPs; microtubule associated proteins; MCAK; mitotic centromere associated kinesin; Ptx; paclitaxelTubulin; Mitosis; Paclitaxel; Microtubule detachment; Microtubule dynamics; Cell motility
New insights into mechanisms of resistance to microtubule inhibitors
by Anutosh Ganguly; Fernando Cabral (pp. 164-171).
Mechanisms to explain tumor cell resistance to drugs that target the microtubule cytoskeleton have relied on the assumption that the drugs act either to suppress microtubule dynamics or to perturb the balance between assembled and nonassembled tubulin. Recently, however, it was found that these drugs also alter the stability of microtubule attachment to centrosomes, and do so at the same concentrations that are needed to inhibit cell division. Based on this new information, a new model is presented that explains resistance resulting from a variety of molecular changes that have been reported in the literature. The improved understanding of drug action and resistance has important implications for chemotherapy with these agents.
Keywords: Abbreviations; CHO; Chinese hamster ovary; Cmd; colcemid; MAPs; microtubule associated proteins; MCAK; mitotic centromere associated kinesin; Ptx; paclitaxelTubulin; Mitosis; Paclitaxel; Microtubule detachment; Microtubule dynamics; Cell motility
Vitamin D and cancer: Deciphering the truth
by Simone Mocellin (pp. 172-178).
Vitamin D is a hormone-like micronutrient involved not only in calcium metabolism but also in a variety of biological activities (e.g., cell proliferation, apoptosis, angiogenesis, inflammation) that makes it a candidate anticancer agent. Preclinical studies support the therapeutic potential of vitamin D both alone and in combination with other therapeutics. Overall, epidemiological data suggest the existence of a link between vitamin D and cancer risk, whereas the results of clinical trials are quite conflicting.This article is a comprehensive and balanced overview of the current evidence in an attempt to critically interpret the wealth of scientific data thus far produced on this research field and to rationally envisage the next steps necessary to define the role of vitamin D in the therapeutic management of cancer.
Keywords: Abbreviations; AIF; apoptosis-inducing factor; CDK; cyclin-dependent kinase; COX-2; cyclo-oxygenase 2; E2F1; E2F transcription factor 1; HIF1a; hypoxia inducible factor 1 alpha; hTERT; human telomerase reverse transcriptase; IL-8; interleukin-8; NFkB; nuclear factor kappa B; pRB; retinoblastma protein; RXR; retinoid X receptor; VDR; vitamin D receptor; VEGF; vascular endothelium growth factorVitamin D; Cancer; Therapy; Prevention; Tumor biology; Meta-analysis
Vitamin D and cancer: Deciphering the truth
by Simone Mocellin (pp. 172-178).
Vitamin D is a hormone-like micronutrient involved not only in calcium metabolism but also in a variety of biological activities (e.g., cell proliferation, apoptosis, angiogenesis, inflammation) that makes it a candidate anticancer agent. Preclinical studies support the therapeutic potential of vitamin D both alone and in combination with other therapeutics. Overall, epidemiological data suggest the existence of a link between vitamin D and cancer risk, whereas the results of clinical trials are quite conflicting.This article is a comprehensive and balanced overview of the current evidence in an attempt to critically interpret the wealth of scientific data thus far produced on this research field and to rationally envisage the next steps necessary to define the role of vitamin D in the therapeutic management of cancer.
Keywords: Abbreviations; AIF; apoptosis-inducing factor; CDK; cyclin-dependent kinase; COX-2; cyclo-oxygenase 2; E2F1; E2F transcription factor 1; HIF1a; hypoxia inducible factor 1 alpha; hTERT; human telomerase reverse transcriptase; IL-8; interleukin-8; NFkB; nuclear factor kappa B; pRB; retinoblastma protein; RXR; retinoid X receptor; VDR; vitamin D receptor; VEGF; vascular endothelium growth factorVitamin D; Cancer; Therapy; Prevention; Tumor biology; Meta-analysis
O6-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry
by Markus Christmann; Barbara Verbeek; Wynand P. Roos; Bernd Kaina (pp. 179-190).
O6-Methylguanine-DNA methyltransferase (MGMT) is a suicide enzyme that repairs the pre-mutagenic, pre-carcinogenic and pre-toxic DNA damage O6-methylguanine. It also repairs larger adducts on the O6-position of guanine, such as O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine and O6-chloroethylguanine. These adducts are formed in response to alkylating environmental pollutants, tobacco-specific carcinogens and methylating (procarbazine, dacarbazine, streptozotocine, and temozolomide) as well as chloroethylating (lomustine, nimustine, carmustine, and fotemustine) anticancer drugs. MGMT is therefore a key node in the defense against commonly found carcinogens, and a marker of resistance of normal and cancer cells exposed to alkylating therapeutics. MGMT also likely protects against therapy-related tumor formation caused by these highly mutagenic drugs. Since the amount of MGMT determines the level of repair of toxic DNA alkylation adducts, the MGMT expression level provides important information as to cancer susceptibility and the success of therapy. In this article, we describe the methods employed for detecting MGMT and review the literature with special focus on MGMT activity in normal and neoplastic tissues. The available data show that the expression of MGMT varies greatly in normal tissues and in some cases this has been related to cancer predisposition. MGMT silencing in tumors is mainly regulated epigenetically and in brain tumors this correlates with a better therapeutic response. Conversely, up-regulation of MGMT during cancer treatment limits the therapeutic response. In malignant melanoma, MGMT is not related to the therapeutic response, which is due to other mechanisms of inherent drug resistance. For most cancers, studies that relate MGMT activity to therapeutic outcome following O6-alkylating drugs are still lacking.
Keywords: MGMT; O; 6; -methylguanine-DNA methyltransferase; Alkyltransferase; Promoter methylation; DNA repair; Drug resistance
O6-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry
by Markus Christmann; Barbara Verbeek; Wynand P. Roos; Bernd Kaina (pp. 179-190).
O6-Methylguanine-DNA methyltransferase (MGMT) is a suicide enzyme that repairs the pre-mutagenic, pre-carcinogenic and pre-toxic DNA damage O6-methylguanine. It also repairs larger adducts on the O6-position of guanine, such as O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine and O6-chloroethylguanine. These adducts are formed in response to alkylating environmental pollutants, tobacco-specific carcinogens and methylating (procarbazine, dacarbazine, streptozotocine, and temozolomide) as well as chloroethylating (lomustine, nimustine, carmustine, and fotemustine) anticancer drugs. MGMT is therefore a key node in the defense against commonly found carcinogens, and a marker of resistance of normal and cancer cells exposed to alkylating therapeutics. MGMT also likely protects against therapy-related tumor formation caused by these highly mutagenic drugs. Since the amount of MGMT determines the level of repair of toxic DNA alkylation adducts, the MGMT expression level provides important information as to cancer susceptibility and the success of therapy. In this article, we describe the methods employed for detecting MGMT and review the literature with special focus on MGMT activity in normal and neoplastic tissues. The available data show that the expression of MGMT varies greatly in normal tissues and in some cases this has been related to cancer predisposition. MGMT silencing in tumors is mainly regulated epigenetically and in brain tumors this correlates with a better therapeutic response. Conversely, up-regulation of MGMT during cancer treatment limits the therapeutic response. In malignant melanoma, MGMT is not related to the therapeutic response, which is due to other mechanisms of inherent drug resistance. For most cancers, studies that relate MGMT activity to therapeutic outcome following O6-alkylating drugs are still lacking.
Keywords: MGMT; O; 6; -methylguanine-DNA methyltransferase; Alkyltransferase; Promoter methylation; DNA repair; Drug resistance
Strategies for enhancing antibody delivery to the brain
by Richard T. Frank; Karen S. Aboody; Joseph Najbauer (pp. 191-198).
Antibodies and antibody conjugates have emerged as important tools for cancer therapy. However, a major therapeutic challenge for the use of antibodies is their inability to cross the blood–brain barrier (BBB) to reach tumors localized in the central nervous system (CNS). Multiple methods have been developed to enhance antibody delivery to the CNS, including direct injection, mechanical or biochemical disruption of the BBB, conjugation to a ‘molecular Trojan horse’, cationization, encapsulation in nanoparticles and liposomes, and more recently, stem cell-mediated antibody delivery. In this review, we discuss each of these approaches, highlighting their successes and the obstacles that remain to be overcome.
Keywords: Antibody; Blood-brain barrier; Cancer therapy; Central nervous system; Nanoparticles; Stem cells
Strategies for enhancing antibody delivery to the brain
by Richard T. Frank; Karen S. Aboody; Joseph Najbauer (pp. 191-198).
Antibodies and antibody conjugates have emerged as important tools for cancer therapy. However, a major therapeutic challenge for the use of antibodies is their inability to cross the blood–brain barrier (BBB) to reach tumors localized in the central nervous system (CNS). Multiple methods have been developed to enhance antibody delivery to the CNS, including direct injection, mechanical or biochemical disruption of the BBB, conjugation to a ‘molecular Trojan horse’, cationization, encapsulation in nanoparticles and liposomes, and more recently, stem cell-mediated antibody delivery. In this review, we discuss each of these approaches, highlighting their successes and the obstacles that remain to be overcome.
Keywords: Antibody; Blood-brain barrier; Cancer therapy; Central nervous system; Nanoparticles; Stem cells
Advances in carcinogenesis: A historical perspective from observational studies to tumor genome sequencing and TP53 mutation spectrum analysis
by Thierry Soussi (pp. 199-208).
Tumor sequencing projects have been initiated over the last decade with the promising goal of identifying novel cancer genes and potential therapeutic targets. One of the unexpected findings of these projects was the discovery that cancer genomes contain thousands of passenger mutations that are irrelevant to tumor development and are coselected by a small number of driver mutations that constitute the true selection power in cancer progression. Although often discarded and considered to be irrelevant, the value of passenger mutations should not be underestimated, as they are the most important markers of the exposure to various carcinogens and are essential to assess the etiology of individual tumors.Over the last century, the history of cancer epidemiology evolved in different stages and concepts from occupational observational studies beginning in the 18th century, in vitro and in vivo experimental analyses and cancer gene analyses, such as Ha-ras or TP53. Mutation spectra of passenger mutations from various types of cancers not only confirm the findings of molecular epidemiology analysis, but also reveal novel profiles that will extend this knowledge to single tumors in all types of cancer.
Keywords: Abbreviations; 6,4-PPs; pyrimidine(6–4)pyrimidone photoproducts; AK; Actinic Keratosis; BaP; benzo(a)pyrene; BPDE; benzo(a)pyrene diol epoxide; BCC; Basal cell carcinoma; CPD; cyclobutane pyrimidine dimers; CRC; colorectal carcinoma; ER; estrogen receptor; ERG; ETS related Gene; EZH2; Histone-lysine N-methyltransferase; GBM; Glioblastoma; HCC; hepatocellular carcinoma; HER2; Human Epidermal growth factor Receptor 2; HGMD; Human Gene Mutation Database; ICGC; International Cancer Genome Consortium; NGS; novel generation sequencing; NSCLC; non small cell lung cancer; PR; Progesterone receptor; SCC; Squamous cell carcinoma; TMPRSS2; androgen-regulated trans-membrane protease, serine 2; TP53 RE; TP53 DNA response elementMutation database; TP53 gene mutations; Cancer etiology; Novel generation sequencing; Molecular epidemiology
Advances in carcinogenesis: A historical perspective from observational studies to tumor genome sequencing and TP53 mutation spectrum analysis
by Thierry Soussi (pp. 199-208).
Tumor sequencing projects have been initiated over the last decade with the promising goal of identifying novel cancer genes and potential therapeutic targets. One of the unexpected findings of these projects was the discovery that cancer genomes contain thousands of passenger mutations that are irrelevant to tumor development and are coselected by a small number of driver mutations that constitute the true selection power in cancer progression. Although often discarded and considered to be irrelevant, the value of passenger mutations should not be underestimated, as they are the most important markers of the exposure to various carcinogens and are essential to assess the etiology of individual tumors.Over the last century, the history of cancer epidemiology evolved in different stages and concepts from occupational observational studies beginning in the 18th century, in vitro and in vivo experimental analyses and cancer gene analyses, such as Ha-ras or TP53. Mutation spectra of passenger mutations from various types of cancers not only confirm the findings of molecular epidemiology analysis, but also reveal novel profiles that will extend this knowledge to single tumors in all types of cancer.
Keywords: Abbreviations; 6,4-PPs; pyrimidine(6–4)pyrimidone photoproducts; AK; Actinic Keratosis; BaP; benzo(a)pyrene; BPDE; benzo(a)pyrene diol epoxide; BCC; Basal cell carcinoma; CPD; cyclobutane pyrimidine dimers; CRC; colorectal carcinoma; ER; estrogen receptor; ERG; ETS related Gene; EZH2; Histone-lysine N-methyltransferase; GBM; Glioblastoma; HCC; hepatocellular carcinoma; HER2; Human Epidermal growth factor Receptor 2; HGMD; Human Gene Mutation Database; ICGC; International Cancer Genome Consortium; NGS; novel generation sequencing; NSCLC; non small cell lung cancer; PR; Progesterone receptor; SCC; Squamous cell carcinoma; TMPRSS2; androgen-regulated trans-membrane protease, serine 2; TP53 RE; TP53 DNA response elementMutation database; TP53 gene mutations; Cancer etiology; Novel generation sequencing; Molecular epidemiology
RAD51 as a potential biomarker and therapeutic target for pancreatic cancer
by Nagaraj S. Nagathihalli; Ganesh Nagaraju (pp. 209-218).
Chemotherapy is a very important therapeutic strategy for cancer treatment. The failure of conventional and molecularly targeted chemotherapeutic regimes for the treatment of pancreatic cancer highlights a desperate need for novel therapeutic interventions. Chemotherapy often fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Overexpression of RAD51 protein, a key player in DNA repair/recombination has been observed in many cancer cells and its hyperexpression is implicated in drug resistance. Recent studies suggest that RAD51 overexpression contributes to the development, progression and drug resistance of pancreatic cancer cells. Here we provide a brief overview of the available pieces of evidence in support of the role of RAD51 in pancreatic tumorigenesis and drug resistance, and hypothesize that RAD51 could serve as a potential biomarker for diagnosis of pancreatic cancer. We discuss the possible involvement of RAD51 in the drug resistance associated with epithelial to mesenchymal transition and with cancer stem cells. Finally, we speculate that targeting RAD51 in pancreatic cancer cells may be a novel approach for the treatment of pancreatic cancer.
Keywords: Pancreatic cancer; Drug resistance; RAD51; DNA repair; Biomarker; Genome instability
RAD51 as a potential biomarker and therapeutic target for pancreatic cancer
by Nagaraj S. Nagathihalli; Ganesh Nagaraju (pp. 209-218).
Chemotherapy is a very important therapeutic strategy for cancer treatment. The failure of conventional and molecularly targeted chemotherapeutic regimes for the treatment of pancreatic cancer highlights a desperate need for novel therapeutic interventions. Chemotherapy often fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Overexpression of RAD51 protein, a key player in DNA repair/recombination has been observed in many cancer cells and its hyperexpression is implicated in drug resistance. Recent studies suggest that RAD51 overexpression contributes to the development, progression and drug resistance of pancreatic cancer cells. Here we provide a brief overview of the available pieces of evidence in support of the role of RAD51 in pancreatic tumorigenesis and drug resistance, and hypothesize that RAD51 could serve as a potential biomarker for diagnosis of pancreatic cancer. We discuss the possible involvement of RAD51 in the drug resistance associated with epithelial to mesenchymal transition and with cancer stem cells. Finally, we speculate that targeting RAD51 in pancreatic cancer cells may be a novel approach for the treatment of pancreatic cancer.
Keywords: Pancreatic cancer; Drug resistance; RAD51; DNA repair; Biomarker; Genome instability
Colorectal cancers choosing sides
by Cristina Albuquerque; Elvira R.M. Bakker; Wendy van Veelen; Ron Smits (pp. 219-231).
In contrast to the majority of sporadic colorectal cancer which predominantly occur in the distal colon, most mismatch repair deficient tumours arise at the proximal side. At present, these regional preferences have not been explained properly. Recently, we have screened colorectal tumours for mutations in Wnt-related genes focusing specifically on colorectal location. Combining this analysis with published data, we propose a mechanism underlying the side-related preferences of colorectal cancers, based on the specific acquired genetic defects in β-catenin signalling.
Keywords: Wnt/β-catenin signalling; Colorectal cancer; APC; Mismatch repair; Tumour location; Signalling dosage
Colorectal cancers choosing sides
by Cristina Albuquerque; Elvira R.M. Bakker; Wendy van Veelen; Ron Smits (pp. 219-231).
In contrast to the majority of sporadic colorectal cancer which predominantly occur in the distal colon, most mismatch repair deficient tumours arise at the proximal side. At present, these regional preferences have not been explained properly. Recently, we have screened colorectal tumours for mutations in Wnt-related genes focusing specifically on colorectal location. Combining this analysis with published data, we propose a mechanism underlying the side-related preferences of colorectal cancers, based on the specific acquired genetic defects in β-catenin signalling.
Keywords: Wnt/β-catenin signalling; Colorectal cancer; APC; Mismatch repair; Tumour location; Signalling dosage
Potential efficacy of cell-penetrating peptides for nucleic acid and drug delivery in cancer
by Azam Bolhassani (pp. 232-246).
Cell penetrating peptides (CPPs) are short amphipathic and cationic peptides that are rapidly internalized across cell membranes. They can be used to deliver molecular cargo, such as imaging agents (fluorescent dyes and quantum dots), drugs, liposomes, peptide/protein, oligonucleotide/DNA/RNA, nanoparticles and bacteriophage into cells. The utilized CPP, attached cargo, concentration and cell type, all significantly affect the mechanism of internalization. The mechanism of cellular uptake and subsequent processing still remains controversial. It is now clear that CPP can mediate intracellular delivery via both endocytic and non-endocytic pathways. In addition, the orientation of the peptide and cargo and the type of linkage are likely important. In gene therapy, the designed cationic peptides must be able to 1) tightly condense DNA into small, compact particles; 2) target the condensate to specific cell surface receptors; 3) induce endosomal escape; and 4) target the DNA cargo to the nucleus for gene expression. The other studies have demonstrated that these small peptides can be conjugated to tumor homing peptides in order to achieve tumor-targeted delivery in vivo. On the other hand, one of the major aims in molecular cancer research is the development of new therapeutic strategies and compounds that target directly the genetic and biochemical agents of malignant transformation. For example, cell penetrating peptide aptamers might disrupt protein–protein interactions crucial for cancer cell growth or survival. In this review, we discuss potential functions of CPPs especially for drug and gene delivery in cancer and indicate their powerful promise for clinical efficacy.Display Omitted
Keywords: Abbreviations; CPP; Cell penetrating peptide; Tat; Trans-acting activator of transcription; HIV-1; Human immunodeficiency virus; PTD; Protein transduction domain; HS; Glycosaminoglycanheparan sulfate; Antp; Aka Penetratin; APC; Antigen presenting cell; ON; Oligonucleotides; HSV-1; Herpes simplex virus type 1; PLL; Poly-; l; -lysine; EBV; Epstein-Barr virus; EBNA1; Epstein-Barr virus nuclear antigen-1; NPCs; Nuclear pore complexes; NLS; Nuclear localization signal; PNA; Peptide-nucleic acid; SV40; Simian virus 40; HnRNP; Heterogeneous nuclear ribonucleoprotein; BHV-1; Bovine herpesvirus 1; RSV; Respiratory syndrome virus; HPV; Human papillomavirus; R; Arginine; K; Lysine; PEI; Polyethylenimine; SCL; Shell-cross-linked; CTT; CPP conjugated therapy; IAP; Inhibitors of apoptosis proteins; Hsp90; Heat-shock protein 90; eNOS; Endothelial nitric oxide synthase; Tat-ELP; Elastin-like polypeptide; ACPP; Activatable cell penetrating peptide; MMP; Matrix metalloproteinase; PEG; Polyethylene glycol; SLN; Solid lipid nanoparticles; GFP; Green fluorescent protein; CPM; Cell penetrating macromolecule; CXCR4; CXC chemokine receptor 4; CPPD; CPP-drug; HIF; Hypoxia-inducible factor-1; RCC; Renal-cell cancer; i.p; Intra-peritoneal; DDS; Drug delivery systemDelivery systems; Cell penetrating peptides; Gene therapy; Drug targeting; Cancer
Potential efficacy of cell-penetrating peptides for nucleic acid and drug delivery in cancer
by Azam Bolhassani (pp. 232-246).
Cell penetrating peptides (CPPs) are short amphipathic and cationic peptides that are rapidly internalized across cell membranes. They can be used to deliver molecular cargo, such as imaging agents (fluorescent dyes and quantum dots), drugs, liposomes, peptide/protein, oligonucleotide/DNA/RNA, nanoparticles and bacteriophage into cells. The utilized CPP, attached cargo, concentration and cell type, all significantly affect the mechanism of internalization. The mechanism of cellular uptake and subsequent processing still remains controversial. It is now clear that CPP can mediate intracellular delivery via both endocytic and non-endocytic pathways. In addition, the orientation of the peptide and cargo and the type of linkage are likely important. In gene therapy, the designed cationic peptides must be able to 1) tightly condense DNA into small, compact particles; 2) target the condensate to specific cell surface receptors; 3) induce endosomal escape; and 4) target the DNA cargo to the nucleus for gene expression. The other studies have demonstrated that these small peptides can be conjugated to tumor homing peptides in order to achieve tumor-targeted delivery in vivo. On the other hand, one of the major aims in molecular cancer research is the development of new therapeutic strategies and compounds that target directly the genetic and biochemical agents of malignant transformation. For example, cell penetrating peptide aptamers might disrupt protein–protein interactions crucial for cancer cell growth or survival. In this review, we discuss potential functions of CPPs especially for drug and gene delivery in cancer and indicate their powerful promise for clinical efficacy.Display Omitted
Keywords: Abbreviations; CPP; Cell penetrating peptide; Tat; Trans-acting activator of transcription; HIV-1; Human immunodeficiency virus; PTD; Protein transduction domain; HS; Glycosaminoglycanheparan sulfate; Antp; Aka Penetratin; APC; Antigen presenting cell; ON; Oligonucleotides; HSV-1; Herpes simplex virus type 1; PLL; Poly-; l; -lysine; EBV; Epstein-Barr virus; EBNA1; Epstein-Barr virus nuclear antigen-1; NPCs; Nuclear pore complexes; NLS; Nuclear localization signal; PNA; Peptide-nucleic acid; SV40; Simian virus 40; HnRNP; Heterogeneous nuclear ribonucleoprotein; BHV-1; Bovine herpesvirus 1; RSV; Respiratory syndrome virus; HPV; Human papillomavirus; R; Arginine; K; Lysine; PEI; Polyethylenimine; SCL; Shell-cross-linked; CTT; CPP conjugated therapy; IAP; Inhibitors of apoptosis proteins; Hsp90; Heat-shock protein 90; eNOS; Endothelial nitric oxide synthase; Tat-ELP; Elastin-like polypeptide; ACPP; Activatable cell penetrating peptide; MMP; Matrix metalloproteinase; PEG; Polyethylene glycol; SLN; Solid lipid nanoparticles; GFP; Green fluorescent protein; CPM; Cell penetrating macromolecule; CXCR4; CXC chemokine receptor 4; CPPD; CPP-drug; HIF; Hypoxia-inducible factor-1; RCC; Renal-cell cancer; i.p; Intra-peritoneal; DDS; Drug delivery systemDelivery systems; Cell penetrating peptides; Gene therapy; Drug targeting; Cancer
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