Showing papers in "Cancer and Metastasis Reviews in 2009"
TL;DR: This review has summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.
Abstract: The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.
1,588 citations
TL;DR: Critical steps in this “force journey,” including mechanical contributions to tissue dysplasia, invasion of the ECM, and metastasis are reviewed, and the biophysical basis of this force journey is discussed and recent advances in the measurement of cellular mechanical properties in vitro and in vivo are presented.
Abstract: A cell undergoes many genetic and epigenetic changes as it transitions to malignancy. Malignant transformation is also accompanied by a progressive loss of tissue homeostasis and perturbations in tissue architecture that ultimately culminates in tumor cell invasion into the parenchyma and metastasis to distant organ sites. Increasingly, cancer biologists have begun to recognize that a critical component of this transformation journey involves marked alterations in the mechanical phenotype of the cell and its surrounding microenvironment. These mechanical differences include modifications in cell and tissue structure, adaptive force-induced changes in the environment, altered processing of micromechanical cues encoded in the extracellular matrix (ECM), and cell-directed remodeling of the extracellular stroma. Here, we review critical steps in this “force journey,” including mechanical contributions to tissue dysplasia, invasion of the ECM, and metastasis. We discuss the biophysical basis of this force journey and present recent advances in the measurement of cellular mechanical properties in vitro and in vivo. We end by describing examples of molecular mechanisms through which tumor cells sense, process and respond to mechanical forces in their environment. While our understanding of the mechanical components of tumor growth, survival and motility remains in its infancy, considerable work has already yielded valuable insight into the molecular basis of force-dependent tumor pathophysiology, which offers new directions in cancer chemotherapeutics.
873 citations
TL;DR: Mounting evidence indicates multiple reciprocal interactions of E-cadherin and β-catenin with EMT-inducing transcriptional repressors to stabilize an invasive mesenchymal phenotype of epithelial tumor cells.
Abstract: The embryonic program ‘epithelial-mesenchymal transition’ (EMT) is activated during tumor invasion in disseminating cancer cells. Characteristic to these cells is a loss of E-cadherin expression, which can be mediated by EMT-inducing transcriptional repressors, e.g. ZEB1. Consequences of a loss of E-cadherin are an impairment of cell-cell adhesion, which allows detachment of cells, and nuclear localization of β-catenin. In addition to an accumulation of cancer stem cells, nuclear β-catenin induces a gene expression pattern favoring tumor invasion, and mounting evidence indicates multiple reciprocal interactions of E-cadherin and β-catenin with EMT-inducing transcriptional repressors to stabilize an invasive mesenchymal phenotype of epithelial tumor cells.
744 citations
TL;DR: The importance of miRNAs in regulating cellular differentiation and proliferation is not surprising, and their misregulation is linked to cancer.
Abstract: MicroRNAs (miRNAs) are small noncoding, double-stranded RNA molecules that can mediate the expression of target genes with complementary sequences. About 5,300 human genes have been implicated as targets for miRNAs, making them one of the most abundant classes of regulatory genes in humans. MiRNAs recognize their target mRNAs based on sequence complementarity and act on them to cause the inhibition of protein translation by degradation of mRNA. Besides contributing to development and normal function, microRNAs have functions in various human diseases. Given the importance of miRNAs in regulating cellular differentiation and proliferation, it is not surprising that their misregulation is linked to cancer. In cancer, miRNAs function as regulatory molecules, acting as oncogenes or tumor suppressors. Amplification or overexpression of miRNAs can down-regulate tumor suppressors or other genes involved in cell differentiation, thereby contributing to tumor formation by stimulating proliferation, angiogenesis, and invasion; i.e., they act as oncogenes. Similarly, miRNAs can down-regulate different proteins with oncogenic activity; i.e., they act as tumor suppressors. This review will highlight the recent discoveries regarding miRNAs and their importance in cancer.
625 citations
TL;DR: The intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.
Abstract: Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.
553 citations
TL;DR: Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia, which are downstream effectors of Rho mediating Rho action on the actin cytoskeleton.
Abstract: The Rho subgroup of the Rho GTPases consisting of RhoA, RhoB and RhoC induces a specific type of actin cytoskeleton and carry out a variety of functions in the cell. mDia and ROCK are downstream effectors of Rho mediating Rho action on the actin cytoskeleton; mDia produces actin filaments by nucleation and polymerization and ROCK activate myosin to cross-link them for induction of actomyosin bundles and contractility. mDia is potentially linked to Rac activation and membrane ruffle formation through c-Src-induced phosphorylation of focal adhesion proteins, and ROCK antagonizes this mDia action. Thus, cell morphogenesis, adhesion, and motility can be determined by the balance between mDia and ROCK activities. Though they are not oncogenes by themselves, overexpression of RhoA and RhoC are often found in clinical cancers, and RhoC has been repeatedly identified as a gene associated with metastasis. The Rho-ROCK pathway is implicated in Ras-mediated transformation, the amoeboid movement of tumor cells in the three-dimensional matrix, and transmigration of tumor cells through the mesothelial monolayer. On the other hand, the Rho-mDia1 pathway is implicated in Src-mediated remodeling of focal adhesions and migration of tumor cells. There is also an indication that the Rho pathway other than ROCK is involved in Src-mediated induction of podosome and regulation of matrix metalloproteases. Thus, Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia.
513 citations
TL;DR: This volume brings together those interested in understanding the contribution of the actin and microtubule cytoskeletons to the cell biology of cancer.
Abstract: Cancer is a disease in which many of the characteristics of normal cell behavior are lost or perturbed. Uncontrolled cell proliferation and inappropriate cell survival are common features of all cancers, but in addition defects in cellular morphogenesis that lead to tissue disruption, the acquisition of inappropriate migratory and invasive characteristics and the generation of genomic instability through defects in mitosis also accompany progression of the disease. This volume is focused on the actin and microtubule cytoskeletons, key players that underpin these cellular processes. Actin and tubulin form highly versatile, dynamic polymers that are capable of organizing cytoplasmic organelles and intracellular compartments, defining cell polarity and generating both pushing and contractile forces. In the cell cycle, these two cytoskeletal structures drive chromosomal separation and cell division. During morphogenesis, they determine cell shape and polarity, and promote stable cell-cell and cell-matrix adhesions through their interactions with cadherins and integrins, respectively. Finally, during cell migration they generate protrusive forces at the front and retraction forces at the rear. These are all aspects of cell behavior than often go awry in cancer. This volume brings together those interested in understanding the contribution of the actin and microtubule cytoskeletons to the cell biology of cancer.
459 citations
TL;DR: The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.
Abstract: Epithelial-to-mesenchymal transition (EMT) is a process that plays essential roles in development and wound healing that is characterized by loss of homotypic adhesion and cell polarity and increased invasion and migration. At the molecular level, EMT is characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin expression (Zeb-1, Zeb-2, Twist, Snail, and Slug). Early work established that loss of E-cadherin and increased expression of MMP-9 was associated with a poor clinical outcome in patients with urothelial tumors, suggesting that EMT might also be associated with bladder cancer progression and metastasis. More recently, we have used global gene expression profiling to characterize the molecular heterogeneity in human urothelial cancer cell lines (n = 20) and primary patient tumors, and unsupervised clustering analyses revealed that the cells naturally segregate into two discrete “epithelial” and “mesenchymal” subsets, the latter consisting entirely of muscle-invasive tumors. Importantly, sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) or type-3 fibroblast growth factor receptor (FGFR3) was confined to the “epithelial” subset, and sensitivity to EGFR inhibitors could be reestablished by micro-RNA-mediated molecular reversal of EMT. The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.
338 citations
TL;DR: The biology and the state of the art management of OS is reviewed and new experimental drugs and potential therapies targeting molecular pathways of OS are discussed.
Abstract: Osteosarcoma (OS) is a class of cancer originating from bone, mainly afflicting children or young adults. It is the second highest cause of cancer-related death in these age groups, mainly due to development of often fatal metastasis, usually in the lungs. Survival for these patients is poor despite the aggressive use of surgery, chemotherapy, and/or radiotherapy. Thus, new effective drugs and other forms of therapy are needed. This article reviews the biology and the state of the art management of OS. New experimental drugs and potential therapies targeting molecular pathways of OS are also discussed.
307 citations
TL;DR: This chapter discusses how coordinated ECM deposition and remodeling is necessary for mammary gland development, how the ECM provides structural and biochemical cues necessary for tissue-specific function, and the role of the cytoskeleton in mediating the extra—to intracellular dialogue occurring between the nucleus and the microenvironment.
Abstract: Mammary gland development, functional differentiation, and homeostasis are orchestrated and sustained by a balance of biochemical and biophysical cues from the organ’s microenvironment. The three-dimensional microenvironment of the mammary gland, predominantly ‘encoded’ by a collaboration between the extracellular matrix (ECM), hormones, and growth factors, sends signals from ECM receptors through the cytoskeletal intracellular matrix to nuclear and chromatin structures resulting in gene expression; the ECM in turn is regulated and remodeled by signals from the nucleus. In this chapter, we discuss how coordinated ECM deposition and remodeling is necessary for mammary gland development, how the ECM provides structural and biochemical cues necessary for tissue-specific function, and the role of the cytoskeleton in mediating the extra—to intracellular dialogue occurring between the nucleus and the microenvironment. When operating normally, the cytoskeletal-mediated dynamic and reciprocal integration of tissue architecture and function directs mammary gland development, tissue polarity, and ultimately, tissue-specific gene expression. Cancer occurs when these dynamic interactions go awry for an extended time.
307 citations
TL;DR: Pericellular proteolysis is integral to the migration cycle and serves to widen ECM gaps and thereby lowers physical stress upon the cell body, which ultimately leads to aligned higher-oder ECM patterns.
Abstract: Cell migration is a multi-step process that leads to the actin-driven translocation of cells on or through tissue substrate. Basic steps involved in cell migration have been defined for two-dimensional haptokinetic migration which, however, does not provide physical constraints imposed by three-dimensional interstitial tissues. We here describe the process of pericellular proteolysis that leads to extracellular matrix (ECM) degradation and realignment during cell movement and integrate it into established steps of cell migration. After actin-driven leading edge protrusion (step I) and anterior formation of integrin-mediated focal interactions to the substrate (step II), ECM breakdown is focalized towards physical ECM barriers several micrometer rearward of the leading edge (step III). Actomyosin-mediated cell contraction (step IV) then leads to rear-end retraction and forward sliding of cell body and nucleus so that a small tube-like matrix defect bordered by realigned ECM fibers becomes apparent (step V). Pericellular proteolysis is thus integral to the migration cycle and serves to widen ECM gaps and thereby lowers physical stress upon the cell body, which ultimately leads to aligned higher-oder ECM patterns.
TL;DR: Paks are overexpressed and/or hyperactivated in several human tumors and their role in cell transformation makes them attractive therapeutic targets, and Pak-targeted therapeutics may efficiently inhibit certain types of tumors and efforts to identify selective Pak-inhibitors are underway.
Abstract: Some of the characteristics of cancer cells are high rates of cell proliferation, cell survival, and the ability to invade surrounding tissue. The cytoskeleton has an essential role in these processes. Dynamic changes in the cytoskeleton are necessary for cell motility and cancer cells are dependent on motility for invasion and metastasis. The signaling pathways behind the reshaping and migrating properties of the cytoskeleton in cancer cells involve a group of Ras-related small GTPases and their effectors, including the p21-activated kinases (Paks). Paks are a family of serine/threonine protein kinases comprised of six isoforms (Pak 1-6), all of which are direct targets of the small GTPases Rac and Cdc42. Besides their role in cytoskeletal dynamics, Paks have recently been shown to regulate various other cellular activities, including cell survival, mitosis, and transcription. Paks are overexpressed and/or hyperactivated in several human tumors and their role in cell transformation makes them attractive therapeutic targets. Pak-targeted therapeutics may efficiently inhibit certain types of tumors and efforts to identify selective Pak-inhibitors are underway.
TL;DR: The regulation of versican expression may represent one mechanism whereby cancer cells alter their surrounding microenvironment to facilitate the malignant growth and invasion of several tumor types.
Abstract: Increased expression of the proteoglycan, versican is strongly associated with poor outcome for many different cancers. Depending on the cancer type, versican is expressed by either the cancer cells themselves or by stromal cells surrounding the tumor. Versican plays diverse roles in cell adhesion, proliferation, migration and angiogenesis, all features of invasion and metastasis. These wide ranging functions have been attributed to the central glycosaminoglycan-binding region of versican, and to the N-(G1) and C-(G3) terminal globular domains which collectively interact with a large number of extracellular matrix and cell surface structural components. Here we review the recently identified mechanisms responsible for the regulation of versican expression and the biological roles that versican plays in cancer invasion and metastasis. The regulation of versican expression may represent one mechanism whereby cancer cells alter their surrounding microenvironment to facilitate the malignant growth and invasion of several tumor types. A greater understanding of the regulation of versican expression may contribute to the development of therapeutic methods to inhibit versican function and tumor invasion.
TL;DR: Current knowledge will be reviewed here with an emphasis on the many open questions in invadopodia biology, and hopes are high that they may also represent valid biological targets to help advance the anti–cancer drug discovery process.
Abstract: Invasive tumor-derived or transformed cells, cultured on a flat extracellular matrix substratum, extend specialized proteolytically active plasma membrane protrusions. These structures, termed invadopodia, are responsible for the focal degradation of the underlying substrate. Considerable progress has been made in recent years towards understanding the basic molecular components and regulatory circuits and the ultrastructural features of invadopodia. This has generated substantial interest in invadopodia as a paradigm to study the complex interactions between the intracellular trafficking, signal transduction and cytoskeleton regulation machineries; hopes are high that they may also represent valid biological targets to help advance the anti-cancer drug discovery process. Current knowledge will be reviewed here with an emphasis on the many open questions in invadopodia biology.
TL;DR: The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic, creating an opportunity for the development of more selective antimitotics with an improved side effect profile.
Abstract: The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. Due to their specific function in mitosis, targeting these proteins creates an opportunity for the development of more selective antimitotics with an improved side effect profile. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs. Drug discovery efforts in this area have initially focused on the plus-end directed kinesin spindle protein (KSP) and a variety of compounds are currently undergoing clinical testing.
TL;DR: What’s currently known about centrosome clustering mechanisms and potential strategies to target these mechanisms for the selective killing of cancer cells are reviewed.
Abstract: Precise control of centrosome number is crucial for bipolar spindle assembly and accurate transmission of genetic material to daughter cells. Failure to properly control centrosome number results in supernumerary centrosomes, which are frequently found in cancer cells. This presents a paradox: during mitosis, cells with more than two centrosomes are prone to multipolar mitoses and cell death, however, cancer cells possessing extra centrosomes usually divide successfully. One mechanism frequently utilized by cancer cells to escape death caused by multipolar mitoses is the clustering of supernumerary centrosomes into bipolar arrays. An understanding of the molecular mechanisms by which cancer cells can suppress multipolar mitoses is beginning to emerge. Here, we review what's currently known about centrosome clustering mechanisms and discuss potential strategies to target these mechanisms for the selective killing of cancer cells.
TL;DR: Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway.
Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is a critical signal transduction pathway that regulates multiple cellular functions. Aberrant activation of this pathway has been identified in a wide range of cancers. Several pathway components including AKT, PI3K and mTOR represent potential therapeutic targets and many small molecule inhibitors are in development or early clinical trials. The complex regulation of the pathway, together with the multiple mechanisms by which it can be activated, make this a highly challenging pathway to target. For successful inhibition, detailed molecular information on individual tumours will be required and it is already clear that different tumour types show distinct combinations of alterations. Recent results have identified alterations in pathway components PIK3CA, PTEN, AKT1 and TSC1 in bladder cancer, some of which are significantly related to tumour phenotype and clinical behaviour. Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway.
TL;DR: The role of the tumor stroma as a source of new cancer biomarkers is discussed, which highlights a novel view of cancer that treats them as organized organs and stresses the importance of including factors related to the tumorStroma into the diagnostic and therapeutic equation of cancer.
Abstract: In recent years the importance of the tumor stroma for the development, promotion and invasion of cancer is becoming increasingly clear. Besides a malignantly transformed cancer cell, tumors also contains many other cell types, including endothelial cells, fibroblasts and cells of the immune system. These cells together with the cancer cells produce the sum extracellular matrix (ECM) of the tumor. The ECM and the non-malignant cells of the tumor are defined as the "tumor stroma". Just as the malignant cell itself can be the source of substances that can be used as biomarkers of cancer, the tumor stroma contains factors that potentially can be used as biomarkers when treating patients with cancer. In this review we will discuss the role of the tumor stroma as a source of new cancer biomarkers. This concept highlights a novel view of cancer and treats them as organized organs. Additionally, this further stresses the importance of including factors related to the tumor stroma into the diagnostic and therapeutic equation of cancer.
TL;DR: Assessment of NUPR1 from the perspective of its functional role in making cancer cells resistant to the action of conventional chemotherapeutic drugs finds that it appears to have tumor suppressive activity in prostate cancer.
Abstract: NUPR1, or p8 or com1, was first identified from rat pancreas during acute pancreatitis and later as a gene whose expression was upregulated in metastatic breast cancer cells. NUPR1 is a molecule whose expression is upregulated in response to stress and is hence influenced by the host microenvironment. While NUPR1 has been implicated in several diseases, there is no singular biochemical pathway that can be attributed to its role in cancer. NUPR1 has been found to aid the establishment of metastasis and to play a key role in the progression of several malignancies including those of breast, thyroid, brain and pancreas. NUPR1 has been implicated in inducing chemoresistance in pancreatic and breast cancer cells, protecting them from apoptosis and making tumor cells genetically unstable. In prostate cancer, however, NUPR1 appears to have tumor suppressive activity. Understanding the mechanism of action of the multifaceted functions of NUPR1 may open up new dimensions towards creating novel therapies against cancer as well as other pathologies. This review draws on several published studies on NUPR1, mainly in cancer biology, and assesses NUPR1 from the perspective of its functional role in making cancer cells resistant to the action of conventional chemotherapeutic drugs.
TL;DR: This review examines basic aspects of the actin cyoskeleton and how it relates to cell motility, and delineates the characteristics of DLC-1 and other members of its family, and describes how they may have multiple effects on the regulation of cell polarity, actin organization, and cell migration.
Abstract: DLC-1 was originally identified as a potential tumor suppressor. One of the key biochemical functions of DLC-1 is to serve as a GTPase activating protein (GAP) for members of the Rho family of GTPases, particularly Rho A-C and Cdc 42. Since these GTPases are critically involved in regulation of the cytoskeleton and cell migration, it seems clear that DLC-1 will also influence these processes. In this review we examine basic aspects of the actin cyoskeleton and how it relates to cell motility. We then delineate the characteristics of DLC-1 and other members of its family, and describe how they may have multiple effects on the regulation of cell polarity, actin organization, and cell migration.
TL;DR: The results of recent advances of the function of group II PAKs in tumorigenesis and metastasis are summarized as well as opportunities for exploring the unique catalytic domain dynamics of this protein family for the design of group I PAK specific inhibitors are summarized.
Abstract: The p21 activated kinases (PAKs) play an essential role in cell signaling and control a variety of cellular functions including cell motility, survival, angiogenesis and mitosis. PAKs are important regulators in growth factor signaling, cytoskeletal reorganization and growth factor-mediated cell migration. Overexpression of PAKs has been detected in many cancers and linked to increased migration potential, anchorage independent growth and metastasis. Six isoforms of PAKs are expressed in human and based on their regulatory properties they have been classified into group I (PAK1-3) and group II (PAK4-6). Besides the well studied group I family, members of the group II PAKs also emerged as interesting targets for the development of new inhibitors for cancer therapy. The availability of high resolution crystal structures for all group II PAKs and their fundamentally different regulatory properties when compared with group I enzymes has opened new opportunities for rational drug designing strategies. In this review, we summarize the results of recent advances of the function of group II PAKs in tumorigenesis and metastasis as well as opportunities for exploring the unique catalytic domain dynamics of this protein family for the design of group II PAK specific inhibitors.
TL;DR: The basis for current anti-mitotic, anti-cancer, therapy and the potential for Aurora B kinase inhibitors as a new differentiated class of agents—“mitotic drivers” are reviewed.
Abstract: In this article we review the basis for current anti-mitotic, anti-cancer, therapy and the potential for Aurora B kinase inhibitors as a new differentiated class of agents—“mitotic drivers”. We review the current understanding of Aurora B inhibition from basic cell biology to inhibitors currently undergoing clinical trials.
TL;DR: The recent identification of urothelial differentiation programs in uromal carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs.
Abstract: Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose—across the entire spectrum of cancers—investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about “stemness” in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated.
TL;DR: Analysis of data obtained by others indicating that all three UPR branches appear selectively down-regulated in mouse models of prostate tumorigenesis indicates that upregulation of the UPR is thought to provide a growth advantage to tumor cells.
Abstract: Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). The UPR promotes cell survival by adjusting ER protein folding capacity but if homeostasis cannot be re-established, apoptosis is induced. The execution of life/death decisions is regulated by the three UPR branches (IRE1, PERK, ATF6) and their downstream effectors. Events that offset the balance of the UPR branches can have devastating consequences, and UPR misregulation has been correlated with various diseases, including metabolic and neurodegenerative diseases and cancer. In cancer, upregulation of the UPR is thought to provide a growth advantage to tumor cells. In contrast to this prevailing view, we report here an analysis of data obtained by others indicating that all three UPR branches appear selectively down-regulated in mouse models of prostate tumorigenesis.
TL;DR: The genetically engineered mice have improved the molecular definition of the divergent pathways of urothelial tumorigenesis and progression, helped delineate the intricate crosstalk among different genetic alterations within a u rothelium-specific context, identified new prognostic markers and novel therapeutic targets potentially applicable for clinical intervention, and provided in vivo platforms for testing preventive strategies of bladder cancer.
Abstract: Urothelium, one of the slowest cycling epithelia in the body, embodies a unique biological context for cellular transformation. Introduction of oncogenes into or removing tumor suppressor genes from the urothelial cells or a combination of both using the transgenic and/or knockout mouse approaches has provided useful insights into the molecular mechanisms of urothelial transformation and tumorigenesis. It is becoming increasingly clear that over-activation of the receptor tyrosine kinase (RTK) pathway, as exemplified by the constitutively activated Ha-ras oncogene, is both necessary and sufficient to initiate the low-grade, non-invasive urothelial carcinomas. Dosage of the mutated Ha-ras, but not concurrent inactivation of pro-senescence molecules p16Ink4a and p19Arf, dictates whether and when the low-grade urothelial carcinomas arise. Inactivation of both p53 and pRb, a prevailing paradigm previously proposed for muscle-invasive urothelial tumorigenesis, is found to be necessary but insufficient to initiate this urothelial carcinoma variant. Instead, downregulation in p53/pRb co-deficient urothelial cells of p107, a pRb family member, is associated with the genesis of the muscle-invasive bladder cancers. p53 deficiency also seems to be capable of cooperating with that of PTEN in eliciting invasive urothelial carcinomas. The genetically engineered mice have improved the molecular definition of the divergent pathways of urothelial tumorigenesis and progression, helped delineate the intricate crosstalk among different genetic alterations within a urothelium-specific context, identified new prognostic markers and novel therapeutic targets potentially applicable for clinical intervention, and provided in vivo platforms for testing preventive strategies of bladder cancer.
TL;DR: Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors such as lung, breast and prostate, been few in number and largely unsuccessful, with no new agents being registered in the last 20 years.
Abstract: Urothelial cell carcinoma is the fifth most common cancer and the costliest to treat. This is largely because of all new cases, about 70% present as superficial disease and this while rarely fatal, tends to recur, requiring long-term follow-up and repeat interventions. The standard of care, intravesical chemo- and immunotherapy, while effective, is associated with a considerable side-effect profile and approximately 30% of patients either fail to respond to treatment or suffer recurrent disease within 5 years. Muscle-invasive bladder cancer is life threatening, showing modest chemosensitivity, and usually requires radical cystectomy. Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors such as lung, breast and prostate, been few in number and largely unsuccessful, with no new agents being registered in the last 20 years. Hence, bladder cancer represents a considerable opportunity and challenge for molecularly targeted therapy.
TL;DR: The scope of the disease, understanding of the role for BCG in urothelial carcinoma of the bladder, explain the recent discoveries regarding the role of neutrophils and TRAIL in therapy, and theorize on potential future areas of research are reviewed.
Abstract: Intravesical Mycobacterium bovis bacillus Calmette-Guerin (BCG) immunotherapy is a highly effective treatment for carcinoma in situ of the bladder, as well as high-risk nonmuscle invasive urothelial carcinoma of the bladder. Despite over 30 years of clinical experience with BCG, the therapy's mechanism has remained enigmatic. Observations regarding the role of neutrophils in BCG immunotherapy have led to exciting discoveries regarding the potential role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in creating the therapeutic benefit of BCG immunotherapy. In this paper, we will review the scope of the disease, highlight our understanding of the role for BCG in urothelial carcinoma of the bladder, explain the recent discoveries regarding the role of neutrophils and TRAIL in therapy, and theorize on potential future areas of research.
TL;DR: A combination of both a global and pathway-specific approach is needed for the identification and validation of robust marker panels of potential clinical importance in bladder cancer.
Abstract: Carcinoma of the urinary bladder involves alterations in multiple cellular pathways that dictate the pathology of the disease and clinical outcome of the patient. This includes alterations in regulation of the cell cycle, apoptotic mechanisms, signal transduction and tumor angiogenesis. Interrogation of alterations in multiple molecules associated with these pathways is leading to the development of biomarker panels that are capable of predicting an individual patient’s outcome or response to specific treatments. With respect to gene expression profiling, two broad approaches may be identified: a global approach and a pathway-specific approach. The global approach involves a high-throughput effort to profile the entire genome, while the pathway-specific approach quantifies select genes across several pathways. While the former has a high potential for discovery of novel signatures, the latter is important in generating reproducible and concise panels that have the potential for rapid clinical implementation. A combination of both these approaches is needed for the identification and validation of robust marker panels of potential clinical importance in bladder cancer.
TL;DR: Some of the genome-wide association study data, particularly for bladder cancer, are reviewed, and their significance in risk prediction and prognosis is assessed.
Abstract: The advent of the genome era after the completion of the Human Genome Project has resulted in intensive efforts to identify all genetic variants that modify human health and disease, including cancer. The development of genome-wide association study (GWAS) approach has facilitated this goal by unbiased examination of the entire human genome for disease association. Here, we review some of the GWAS data, particularly for bladder cancer, and assess their significance in risk prediction and prognosis. A mechanistic understanding of the risk association through functional studies and phenotypic assays is also discussed. The ultimate goal is the development of a comprehensive risk prediction model which integrates genetic, environment, and person risk factors to benefit disease diagnosis, prevention, and treatment.
TL;DR: The recent finding that ILK also regulates the microtubule cytoskeleton and is involved in mitotic spindle organization means its deregulation may also lead to errors in cell division causing genomic instability, potentially contributing to cancer development.
Abstract: The cytoskeleton is composed of three major constituents: actin filaments, intermediate filaments and microtubules. These are vital for numerous normal cellular processes including cell spreading and migration, intracellular organelle transport, mechanical strength, mitosis and cytokinesis. Deregulation of cytoskeletal components can lead to cells developing several oncogenic phenotypes; for example increased migration and invasiveness, defects in cellular morphogenesis and genetic instabilities due to errors in mitosis and cytokinesis. Integrin-linked kinase (ILK) is a protein with well established roles in regulating actin cytoskeletal reorganization, survival, proliferation, cell migration, invasion and epithelial to mesenchymal transition, and is therefore essential to normal cell physiology. In addition, ILK is overexpressed or deregulated in a number of human cancers and when experimentally overexpressed leads to the acquisition of a number of oncogenic phenotypes, some of which, such as increased cell migration, are actin-dependent. Here we shall focus on the recent finding that ILK also regulates the microtubule cytoskeleton and is involved in mitotic spindle organization. Therefore its deregulation may also lead to errors in cell division causing genomic instability, potentially further contributing to cancer development. In light of these findings, the therapeutic potential of the anti-mitotic effects of genetic or pharmacological inhibition of ILK will also be discussed.