BBA - Reviews on Cancer (v.1766, #1)

IGF-I mediated survival pathways in normal and malignant cells by Raushan T. Kurmasheva; Peter J. Houghton (1-22).
The type-I and -II insulin-like growth factors (IGF-I, II) are now established as survival- or proliferation-factors in many in vitro systems. Of note IGFs provide trophic support for multiple cell types or organ cultures explanted from various species, and delay the onset of programmed cell death (apoptosis) through the mitochondrial (intrinsic pathway) or by antagonizing activation of cytotoxic cytokine signaling (extrinsic pathway). In some instances, IGFs protect against other forms of death such as necrosis or autophagy. The effect of IGFs on cell survival appears to be context specific, being determined both by the cell origin (tissue specific) and the cellular stress that induces loss of cellular viability. In many human cancers, there is a strong association with dysregulated IGF signaling, and this association has been extensively reviewed recently. IGF-regulation is also disrupted in childhood cancers as a consequence of chromosomal translocations. IGFs are implicated also in acute renal failure, traumatic injury to brain tissue, and cardiac disease. This article focuses on the role of IGFs and their cellular signaling pathways that provide survival signals in stressed cells.

Gastrin-releasing peptide and cancer by Oneel Patel; Arthur Shulkes; Graham S. Baldwin (23-41).
Over the past 20 years, abundant evidence has been collected to suggest that gastrin-releasing peptide (GRP) and its receptors play an important role in the development of a variety of cancers. In fact, the detection of GRP and the GRP receptor in small cell lung carcinoma (SCLC), and the demonstration that anti-GRP antibodies inhibited proliferation in SCLC cell lines, established GRP as the prototypical autocrine growth factor. All forms of GRP are generated by processing of a 125-amino acid prohormone; recent studies indicate that C-terminal amidation of GRP18–27 is not essential for bioactivity, and that peptides derived from residues 31 to 125 of the prohormone are present in normal tissue and in tumors. GRP receptors can be divided into four classes, all of which belong to the 7 transmembrane domain family and bind GRP and/or GRP analogues with affinities in the nM range. Over-expression of GRP and its receptors has been demonstrated at both the mRNA and protein level in many types of tumors including lung, prostate, breast, stomach, pancreas and colon. GRP has also been shown to act as a potent mitogen for cancer cells of diverse origin both in vitro and in animal models of carcinogenesis. Other actions of GRP relevant to carcinogenesis include effects on morphogenesis, angiogenesis, cell migration and cell adhesion. Future prospects for the use of radiolabelled and cytotoxic GRP analogues and antagonists for cancer diagnosis and therapy appear promising.
Keywords: Bombesin; GRP; Migration; Proliferation;

Decay-accelerating factor (CD55): A versatile acting molecule in human malignancies by Jan-Henrik Mikesch; Horst Buerger; Ronald Simon; Burkhard Brandt (42-52).
The decay-accelerating factor (DAF, CD55) physiologically serves as an inhibitor of the complement system. Moreover, DAF is broadly expressed in malignant tumors. Here, DAF seems to dispose of several different functions reaching far beyond its immunological role, e.g., promotion of tumorigenesis, decrease of complement mediated tumor cell lysis, autocrine loops for cell rescue and evasion of apoptosis, neoangiogenesis, invasiveness, cell motility, and metastasis via oncogenic tyrosine kinase pathway activation, and specific seven-span transmembrane receptors (CD97) binding. Furthermore, DAF has already been included in diagnostic or therapeutic studies. Thereby, studies applying monoclonal anti-DAF antibodies and anti-DAF vaccination for a targeted therapy have been enrolled recently.
Keywords: Decay-accelerating factor;

Pro-apoptotic role of NF-κB: Implications for cancer therapy by Senthil K. Radhakrishnan; Sitharthan Kamalakaran (53-62).
Nuclear factor-κB (NF-κB) is generally viewed as anti-apoptotic and oncogenic, leading to a quest for its inhibitors. However, recent evidence suggests that in some situations NF-κB may promote apoptosis. Depending on the specific cell type and the stimulus involved, NF-κB activation may lead to either anti- or pro-apoptotic response. Both these effects can be mediated by NF-κB in a context-dependent manner by selectively regulating its target genes. In this review, we discuss the evidence for NF-κB's pro-apoptotic role and explore the possible mechanisms behind it. We emphasize that rather than trying to inhibit NF-κB in cancer therapy, agents should be developed to unleash its pro-apoptotic ability.
Keywords: NF-κB; Apoptosis; Cancer; Drug target;

Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention by Ercole Cavalieri; Dhubajyoti Chakravarti; Joseph Guttenplan; Elizabeth Hart; James Ingle; Ryszard Jankowiak; Paola Muti; Eleanor Rogan; Jose Russo; Richard Santen; Thomas Sutter (63-78).
Exposure to estrogens is associated with increased risk of breast and other types of human cancer. Estrogens are converted to metabolites, particularly the catechol estrogen-3,4-quinones (CE-3,4-Q), that can react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone base excision repair of this damage may lead to the mutations that can initiate breast, prostate and other types of cancer.The reaction of CE-3,4-Q with DNA forms the depurinating adducts 4-hydroxyestrone(estradiol) [4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These two adducts constitute more than 99% of the total DNA adducts formed. Increased levels of these quinones and their reaction with DNA occur when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen activating enzymes and/or deficient expression of the deactivating (protective) enzymes. This unbalanced metabolism has been observed in breast biopsy tissue from women with breast cancer, compared to control women. Recently, the depurinating adduct 4-OHE1(E2)-1-N3Ade has been detected in the urine of prostate cancer patients, but not in urine from healthy men.Mutagenesis by CE-3,4-Q has been approached from two different perspectives: one is mutagenic activity in the lacI reporter gene in Fisher 344 rats and the other is study of the reporter Harvey-ras gene in mouse skin and rat mammary gland. A → G and G → A mutations have been observed in the mammary tissue of rats implanted with the CE-3,4-Q precursor, 4-OHE2. Mutations have also been observed in the Harvey-ras gene in mouse skin and rat mammary gland within 6–12 h after treatment with E2-3,4-Q, suggesting that these mutations arise by error-prone base excision repair of the apurinic sites generated by the depurinating adducts.Treatment of MCF-10F cells, which are estrogen receptor-α-negative immortalized human breast epithelial cells, with E2, 4-OHE2 or 2-OHE2 induces their neoplastic transformation in vitro, even in the presence of the antiestrogen ICI-182,780. This suggests that transformation is independent of the estrogen receptor. The transformed cells exhibit specific mutations in several genes. Poorly differentiated adenocarcinomas develop when aggressively transformed MCF-10F cells are selected and injected into severe combined immune depressed (SCID) mice. These results represent the first in vitro/in vivo model of estrogen-induced carcinogenesis in human breast epithelial cells.In other studies, the development of mammary tumors in estrogen receptor-α knockout mice expressing the Wnt-1 oncogene (ERKO/Wnt-1) provides direct evidence that estrogens may cause breast cancer through a genotoxic, non-estrogen receptor-α-mediated mechanism.In summary, this evidence strongly indicates that estrogens can become endogenous tumor initiators when CE-3,4-Q react with DNA to form specific depurinating adducts. Initiated cells may be promoted by a number of processes, including hormone receptor stimulated proliferation. These results lay the groundwork for assessing risk and preventing disease.
Keywords: Cancer initiation; Carcinogenicity; Cell transformation; Depurinating estrogen-DNA adduct; Estrogens; Mutations;

The Ets transcription factors of the PEA3 group: Transcriptional regulators in metastasis by Yvan de Launoit; Jean-Luc Baert; Anne Chotteau-Lelievre; Didier Monte; Laurent Coutte; Sébastien Mauen; Virginie Firlej; Cindy Degerny; Kathye Verreman (79-87).
The PEA3 group is composed of three highly conserved Ets transcription factors: Erm, Er81, and Pea3. These proteins regulate transcription of multiple genes, and their transactivating potential is affected by post-translational modifications. Among their target genes are several matrix metalloproteases (MMPs), which are enzymes degrading the extracellular matrix during normal remodelling events and cancer metastasis. In fact, PEA3-group genes are often over-expressed in different types of cancers that also over-express these MMPs and display a disseminating phenotype. Experimental regulation of the synthesis of PEA3 group members influences the metastatic process. This suggests that these factors play a key role in metastasis.
Keywords: Metastasis; Transcription factor; Ets; PEA3 group; MMP;

C/EBPα: A tumour suppressor in multiple tissues? by Mikkel Bruhn Schuster; Bo Torben Porse (88-103).
The CCATT/enhancer binding protein alpha, C/EBPα, is a key transcription factor involved in late differentiation events of several cell types. Besides acting as a classical transcription factor, C/EBPα is also a well-characterized inhibitor of mitotic growth in most cell lines tested. In line with its anti-mitotic properties, C/EBPα has been shown to interact with, and alter the activities of, several cell cycle related proteins and a number of models as to the mechanistics of C/EBPα-mediated growth repression have been proposed. More recently, several reports have indicated that C/EBPα acts as a tumour suppressor in the hematopoietic system and that mutation within C/EBPα is sufficient to induce tumourigenesis. Here, we will review these data and probe the possibility that C/EBPα also act as a tumour suppressor in other C/EBPα-expressing tissues.
Keywords: C/EBPα; Tumour suppressor; Leukemia; Cell cycle regulation; Differentiation;

Colorectal cancer is a major cause of mortality and whilst up to 80% of sporadic colorectal tumours are considered preventable, trends toward increasing obesity suggest the potential for a further increase in its worldwide incidence. Novel methods of colorectal cancer prevention and therapy are therefore of considerable importance. Non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive against colorectal cancer, mainly through their inhibitory effects on the cyclooxygenase isoform COX-2. COX enzymes represent the committed step in prostaglandin biosynthesis and it is predominantly increased COX-2-mediated prostaglandin-E2 (PGE2) production that has a strong association with colorectal neoplasia, by promoting cell survival, cell growth, migration, invasion and angiogenesis. COX-1 and COX-2 inhibition by traditional NSAIDs (for example, aspirin) although chemopreventive have some side effects due to the role of COX-1 in maintaining the integrity of the gastric mucosa. Interestingly, the use of COX-2 selective NSAIDs has also shown promise in the prevention/treatment of colorectal cancer while having a reduced impact on the gastric mucosa. However, the prolonged use of high dose COX-2 selective inhibitors is associated with a risk of cardiovascular side effects. Whilst COX-2 inhibitors may still represent viable adjuvants to current colorectal cancer therapy, there is an urgent need to further our understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and hence identify safer, more effective strategies for the prevention of colorectal cancer. In particular, PGE2 synthases and E-prostanoid receptors (EP1–4) have recently attracted considerable interest in this area. It is hoped that at the appropriate stage, selective (and possibly combinatorial) inhibition of the synthesis and signalling of those prostaglandins most highly associated with colorectal tumorigenesis, such as PGE2, may have advantages over COX-2 selective inhibition and therefore represent more suitable targets for long-term chemoprevention. Furthermore, as COX-2 is found to be overexpressed in cancers such as breast, gastric, lung and pancreatic, these investigations may also have broad implications for the prevention/treatment of a number of other malignancies.
Keywords: COX-2; NSAID; Chemoprevention; Colon cancer; EP receptors; Prostaglandin synthases;

The complexity of targeting EGFR signalling in cancer: From expression to turnover by Sinto Sebastian; Jeffrey Settleman; Stephan J. Reshkin; Amalia Azzariti; Antonia Bellizzi; Angelo Paradiso (120-139).
The epidermal growth factor receptor (ErbB1 or EGFR) has been found to be altered in a variety of human cancers. A number of agents targeting these receptors, including specific antibodies directed against the ligand-binding domain of the receptor and small molecules that inhibit kinase activity are either in clinical trials or are already approved for clinical treatment. However, identifying patients that are likely to respond to such treatments has been challenging. As a consequence, it still remains important to identify additional alterations of the tumor cell that contribute to the response to EGFR-targeted agents. While EGFR-mediated signalling pathways have been well established, there is still a rather limited understanding of how intracellular protein–protein interactions, ubiquitination, endocytosis and subsequent degradation of EGFR contribute to the determination of sensitivity to EGFR targeting agents and are emerging areas of investigation. This review primarily focuses on the basic signal transduction pathways mediated through activated membrane bound and/or endosomal EGFR and emphasizes the need to co-target additional proteins that function either upstream or downstream of EGFR to improve cancer therapy.
Keywords: Cancer; EGFR; Cell signalling; Trafficking; Turnover; EGFR inhibitors;

Cell signaling pathways engaged by KSHV by Annika Järviluoma; Päivi M. Ojala (140-158).
Kaposi's sarcoma herpesvirus (KSHV) is the eighth human herpesvirus discovered in 1994 from Kaposi's sarcoma lesion of an AIDS patient. The strong molecular and epidemiological links associating KSHV with Kaposi's sarcoma and certain lymphoproliferative disorders indicate that KSHV is required for the development of these malignancies. Although KSHV is equipped to manipulate and deregulate several cellular signaling pathways, it is not yet understood how this leads to cell transformation. Profound understanding of the interplay of viral and cellular factors in KSHV-infected cells will provide valuable information on the mechanisms of viral tumorigenesis and enable development of efficient targeted therapies for virus-induced cancers. This review focuses on the cellular signaling pathways that KSHV gene products impinge on and discusses their putative contribution to tumorigenesis.
Keywords: KSHV; Signaling pathways; Cancer; Cell cycle; Apoptosis; Immune evasion; Angiogenesis;

Bone marrow-derived cells include haematopoietic cell lineages and the recently described endothelial progenitor cells (EPCs). It has been recently emphasised that these marrow-derived cells contribute to tumour angiogenesis, and different mechanisms have been proposed that account for this activity. Whereas haematopoietic cells may promote tumour angiogenesis through the release of proangiogenic factors or by creating permissive conditions in the tumour microenvironment that favour the growth of locally derived blood vessels (“paracrine” role), endothelial progenitors are thought to directly incorporate into nascent blood vessels as bona fide endothelial cells (“building block” role). The relative contribution of these distinct pathways to tumour angiogenesis is the subject of intense investigation and debate.
Keywords: Tumor angiogenesis; Proangiogenic cell; Hematopoietic cell;