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Tumor and Host Determinants of Pulmonary Metastasis in Bladder Cancer

  • Neveen Said
  • Dan Theodorescu
Chapter

Abstract

Despite the recent advances in the diagnosis of bladder cancer, ­recurrence after surgical intervention for muscle invasive disease is still problematic as nearly half of patients harbor occult distant metastases. Clinical data from human disease revealed that, invasive and metastatic bladder cancer cells can metastasize to lungs, and this in turn is associated with poor 5-year survival rate. Experimental rodent models of carcinogenesis and metastasis are available to study this phenomenon. Comparative gene expression profiling, proteomic and computational studies identified an intertwined network of metastasis promoters and suppressors that modulate the interactions between the components of the pulmonary milieu and cancer cells inflammatory mediators, ECM molecules, as well as peptide hormones. In this chapter we provide select exemplar of some of the molecular mechanisms underlying lung colonization by bladder cancer.

Keywords

Bladder Cancer Bladder Cancer Cell Urothelial Cancer Human Bladder Cancer Bladder Cancer Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

14.1 Introduction

Urothelial cancer (UC) is the most common malignancy affecting the urinary ­system. When it affects the bladder, it leads to an estimated 70,530 new cases in the United States, with a male to female ratio of 3:1 and approximately 14,680 deaths, expected in 2010 [1]. UC arises from the mucosal lining and is frequently ­multifocal. Numerous factors, including chromosomal markers, genetic ­polymorphisms, and genetic and epigenetic alterations may be involved in tumorigenesis, progression and metastasis. At initial presentation, 70% of patients with UC present with non-muscle invasive (formerly known as “superficial”), and 30% present with muscle invasive disease [2]. Despite a good prognosis for patients with the former, recurrence is common and is associated with development of muscle invasive disease in up to 30%. Also, 50% of patients presenting with muscle invasive UC develop distant metastases leading to poor 5-year survival rate [1]. Clinical data from human disease as well as experimental rodent models of carcinogenesis and metastasis reveals that when it occurs, metastasis of this tumor is commonly found in the regional lymph node metastasis and the lungs. Given that metastases are responsible for most of the deaths from this disease [3, 4], understanding of the process will aid in the development of new approaches for treatment.

14.2 Multistep Process of Metastasis

The high incidence of pulmonary metastases in cancer patients was initially believed to be a random process based on blood flow predominance as lungs receive significant cardiac output [5, 6]. This was supported by the observation that metastases often initiate in pulmonary arterioles and later traverse the basement membrane into the lung parenchyma [6, 7]. However, growing body of literature supports the patterns of metastases is also a consequence of the “seed and soil” theory put forth by Stephen Paget in 1889 [8]. Hence, the development of lung metastasis is likely an active highly selective process instigated by tumor cells, and is strongly influenced by the interactions between tumor and host cells, and by both the immediate and extended tumor microenvironments [3, 7, 8, 9, 10, 11, 12, 13, 14].

14.2.1 The Lung Microenvironment as a Host for Metastatic Tumor Cells

Barriers created by the lung microenvironment include physical barriers such as vascular endothelium, extracellular matrix (ECM) components and basement ­membranes, as well as physiologic barriers such as limited oxygen (hypoxia) and nutrients, and immunologic barriers by the immune system [9, 15]. The vascular endothelium is a critical regulator of pulmonary function and its phenotype is modulated by myriad stimuli such as proinflammatory cytokines and hemodynamic forces thereby impacting the development of vascular disease states [15]. Metastatic progression also depends on cancer cell secretome as both the growing primary tumor and shed tumor cells in the circulation (Fig. 14.1), secrete ­inflammatory mediators that triggers vascular inflammation in the lungs that is characterized by recruitment of bone marrow derived myeloid cells, margination, extravasation, and activation of circulating mononuclear cells into vessel walls to lung parenchyma [10, 12, 13, 14, 16, 17, 18, 19]. This multistep process is the result of local and systemic secretion of chemotactic factors, macrophage-activating cytokines, endothelin-1, reactive oxygen species (ROS), growth factors, upregulation of vascular adhesion molecules, and production of MMPs. The buildup of an inflammatory microenvironment, generates a premetastatic niche with progressive pulmonary vascular inflammation hospitable for metastatic growth [10, 12, 13, 14, 18, 19]. The activation of endothelial cells (ECs) is a crucial step in pulmonary vascular inflammation, and can result in subsequent increase in surface expression of cell adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion ­molecule (ICAM)-1, and selectins, which contribute to the recruitment of inflammatory cells to ECs and their transmigration across the vascular wall [18, 20]. In turn, activated ECs secrete cytokines and chemokines such as monocyte chemotactic protein 1 (MCP-1), which is a potent inducer for ­monocyte attachment to ECs and ­migration into subendothelial space [21, 22, 23, 24]. Mechanisms leading to proinflammatory cell recruitment to the lung are exploited by circulating cancer cells to extravasate from circulation [20]. These mechanisms include common cell adhesion molecule interactions as well as the expression of inflammatory cytokines/chemokines leading to recruitment and activation of macrophages. Persistent activation of ECs and macrophages, with reciprocal persistent production of cytokines and ROS cause local chronic inflammation that promotes increased homing of tumor cells to the lungs [21, 22, 23, 24] as well as activation of non-tumor cells in tumor lesions stimulating tumor angiogenesis, invasiveness and intravasation/extravasation. Interestingly, a strong body of literature highlighted the central importance of nuclear factor-κB (NF-κB) in the activation of and cross-talk between all the cell types involved [22, 23, 24].
Fig. 14.1

A view of the multistep process of metastasis: Disseminated cancer cells in the circulation arise from highly invasive cell populations in the primary tumor that invade the blood vessel wall, intravasate and circulate in the blood stream. Secreted tumor factors “cancer secretome” form invasive cancer cells in the primary tumors and circulating tumor cells recruit, bone marrow-derived myeloid cells, to the prospective metastatic site “lungs”. In turn, myeloid cells acquire an inflammatory macrophage phenotype, secreting factors “macrophage secretome” and contribute to the construction of a pre-metastatic niche favorable for implantation and growth of disseminating tumor cells forming micro- and macro-metastases

The premetastatic niche may also be responsible for metastases to specific organs. The key tumor-secreted factors that determine metastatic sites and mediate premetastatic niche formation have yet to be identified, although the roles for cytokines/chemokines, MMPs and growth factors’ signaling in pulmonary endothelial cells and macrophages have been reported [25, 26]. These make the lung microenvironment more receptive to cancers cells. We have recently reported the roles of endothelin-1 in as an important mediator of lung inflammation and colonization of bladder cancer cells (discussed below) [14]. Elevated fibronectin expression by fibroblasts and fibroblast-like cells resident at premetastatic sites seems to be an important factor in the development of the premetastatic niche [12]. In addition, the secretion of versican by tumor cells and subsequently by inflammatory macrophages has been recently found to play a role in lung metastasis [10, 16, 27].

Overexpression of tumor-derived immunosuppressive factors such as TGFβ, VEGF, IL-6, MCP1/CCL2, MMPs and Cox-2/prostanoids in the inflammatory premetastatic niche dampens the tumor-suppressing activities of cells responsible of immune surveillance as natural killer cells and antigen-presenting cells and supports an inflammatory phenotype of tumor-associated macrophages, TAM; promote tumor progression by secreting growth factors and cytokines that stimulate tumor metastases [16, 17, 28]. TAMs can facilitate tumor formation and progression by activation of NF-κB and AP-1 [16, 17, 29], and are especially attracted to regions of hypoxia, where they secrete angiogenic inducers and proteases, and express high levels of the HIF-1 and -2 transcription factors [18, 30, 31, 32] that further augment macrophage recruitment and activation as well as tumor cell invasiveness. Furthermore, TAMs can release growth factors such as PDGF, EGF, cytokines/chemokines, and MMPs which enhance proliferation, survival, and invasion of tumor cells as well as secrete and induce secretion of ECM proteoglycans such as versican from tumor cells and fibroblasts in the lung milieu further augmenting invasiveness, inflammation and metastasis [10, 23, 33, 34, 35, 36, 37, 38].

Our laboratory has identified two major molecules implicated in bladder cancer metastasis to the lungs, the metastasis suppressor RhoGDI2 and the pro-metastatic Ral A/B.

14.2.2 The Metastasis Suppressor RhoGDI2

Rho family GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been identified as functional metastasis suppressor during studies of the differential invasive and metastatic properties of isogenic human bladder carcinoma cell lines, T24 (non-­metastatic), and T24T (highly invasive and metastatic) using experimental metastasis models and comparative genomic studies [39]. RhoGDI2 was also found to be a prognostic marker in patients after cystectomy that its reduced expression was associated with decreased patient survival. However, approximately 35% of patients with moderate or high levels of RhoGDI2 protein-developed metastatic disease ­suggesting that not only the expression level, but other mechanisms might regulate the metastasis suppressor effect of RhoGDI2 [40]. Phosphorylation, binding to specific partners, truncations, proteolytic cleavage, or change in subcellular localization was considered given the existing data on the other members of the RhoGDI family (reviewed in [41]). Comparative gene expression profiling of human bladder cancer tissues and cell lines identified that the down-stream effectors downregulated by RhoGDI2 are molecules that have long been implicated in pulmonary vascular diseases: Endothelin-1 (ET-1) [42] and versican [14, 27, 43].

14.2.3 Endothelin Axis

ET-1, an endothelial cell-derived vasoconstrictor peptide is an important member of the endothelin axis with myriad developmental, physiological and pathological functions [29, 44, 45, 46]. The “Endothelin Axis” consists of three similar small peptides, ET-1, ET-2 and ET-3, two G-protein-coupled receptors, ETAR and ETBR, and two membrane-bound proteases, the ET-converting enzymes, ECE-1 and ECE-2 [44], that activate the secreted pro forms of the peptide. ET-1 production is stimulated by a variety of cytokines and growth factors, hypoxia, and shear stress, while ETAR activation triggers signaling networks involved in cell proliferation, new vessel formation, invasion, inflammation, and metastatic spread [44, 47, 48, 49]. In benign and malignant diseases, ET-1 has been shown to activate the pro-inflammatory transcriptional factors AP-1 and NF-κB in human monocytes and cancer cells (Fig. 14.2) and to stimulate the production of inflammatory cytokines IL-6, MCP-1 and Cox2, as well as MMP activity, the key orchestrators of inflammation-mediated cancer cell invasiveness and metastasis [50, 51, 52, 53]. Recently, gene expression data and immunostaining of from human bladder cancer has revealed that ET-1 and ETAR are over-expressed in muscle invasive disease, and that the expression level is associated with reduced patient survival [14]. Experimental and spontaneous metastasis models revealed that tumor ET-1 triggers inflammation in the lungs wherein inflammatory cells, primarily macrophages, enhance and facilitate the process of metastatic colonization [14]. The magnitude of this early inflammatory response determines the kinetics of subsequent development of lung metastases. This inflammatory response is likely triggered by tumor secretion of ET-1 and the pro-inflammatory cytokines IL-6 and MCP-1. Interestingly, targeting ET-1 gene in tumor cells or pharmacologic inhibition of ETAR prior to injection of tumor cells reduced the early inflammatory response, both tumor and host MCP-1/CCL2, IL-6 and Cox-2 in the lung microenvironment and subsequent metastatic colonization. In contrast, when the early inflammatory response was allowed to develop upon injection of tumor cells, then later followed by ETAR blockade, the reduction of lung inflammation and clinical lung metastases was not as dramatic. Depletion of macrophages also significantly reduced the inflammatory response and the ensuing lung metastases.
Fig. 14.2

Multiple pathways of endothelin involvement in lung metastasis: (a) Binding of ET-1 to the ETA receptor in the plasma membrane triggers signal-transduction pathways in both cancer cells and macrophages that converge in activation of NF-κB and AP-1 transcription factors. (b) Schematic illustration of the roles of ET-1 in bladder cancer metastasis to the lungs

14.2.4 Versican

Versican, a chondroitin sulfate proteoglycan, is a major structural component of the ECM (Fig. 14.3). Differential RNA splicing gives rise to four isoforms of versican (V0, V1, V2, and V3), which vary by the presence or absence of two glycosaminoglycan (GAG) binding domains named αGAG and βGAG. The various domains of versican form highly hydrated complexes that trap cytokines, enzymes, growth factors, lipoproteins, other extracellular matrix molecules, and signaling receptors. It is implicated in the pathogenesis of pulmonary vascular diseases and atherosclerosis, causing an ECM expansion, fostering pro-inflammatory cytokines and cells and dramatically influencing the inflammatory phenotype of cellular components of these diseases [54].
Fig. 14.3

Structure of versican and its interactions: The N-terminal, G1 domain is composed of an immunoglobulin (Ig)-like motif, followed by two proteoglycan tandem repeats that bind to hyaluronan. The C-terminal, G3 domain, consists of two epidermal growth factor (EGF)-like repeats, a carbohydrate recognition domain (CRD), and a complement binding protein (CBP). Chondroitin sulfate (CS) chain binding regions exist between G1 and G3 consist of a protein core and one or two glycosaminoglycans (α and β GAG) that vary amongst tissues and specific molecules. Different domains of versican bind to and interact with a wide variety of molecules, such as growth factors (TGFβ, PDGF-BB), cytokines, chemokines (MCP-1), adhesion/ECM molecules (selectins, HA, CD44, fibrinogen/fibrin, fibronectin, thrombospondin, collagens), MMPs and LDL

The association between increased levels of versican and progression of cancer to disseminated disease suggests that versican is important in promoting cancer cell proliferation, motility, invasion and metastasis [10, 16, 23, 33, 34, 35, 36, 37, 38, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65]. More recent studies [10] identified cancer cell-secreted versican, as a macrophage activator that acts through TLR2/6 inducing TNF-alpha secretion by myeloid cells, generating an inflammatory microenvironment hospitable for metastatic growth. In vitro functional studies, revealed versican is a key mediator of cancer cell-macrophages cross-talk and significantly inhibited their adhesion to and invasion of ECM molecules as well as pulmonary microvascular endothelial cells [27, 66]. Interestingly, comparative gene expression profiling of invasive/metastatic bladder cancer cells with clinical bladder cancer specimens identified versican as the top upregulated gene, positively correlated with bladder cancer stage and poor prognosis, and in vitro with invasiveness of bladder cancer cell lines [27, 43]. It remains to be seen if genetic manipulation of versican expression in bladder cancer cells, either by stable overexpression or knockdown demonstrates a role of tumor versican in metastasis.

14.2.5 Ral GTPases

The Ras-like family of monomeric G proteins (Ral GTPases), RalA and RalB are paralogs (85% amino acid identity) that participate in diverse cellular functions [67] (Fig. 14.4). These signaling proteins, regulated by multiple pathways including Ras (reviewed in [68]), have been shown to be necessary for cellular phenotypes associated with cancer progression and metastasis. Phosphorylation and subsequent activation, of RalA and RalB is paralog-specific as they are phosphorylated at specific conserved sites by different kinases [69]. PKC phosphorylation of RalB at S198 in bladder cancer cell lines has been recently reported to be necessary for cytoskeletal organization, anchorage-independent growth, and cell migration in vitro and for subcutaneous tumor growth and lung metastasis in vivo [69]. In addition, Ral effector, RalBP1 was found to be highly expressed in bladder cancer patients and necessary for metastasis of human bladder cancer cell lines [70]. In addition RalA and/or RalB have also been shown to regulate transcription factors such as NF-κB and AP-1 [71, 72] and play a role in the regulation of expression of key molecules, including the prognostic marker and cell surface GPI-linked glycoprotein, CD24 [68].
Fig. 14.4

The regulation of Ral and downstream signaling: RalGTPases are activated by a variety of stimuli, including guanidine nucleotide exchange factors (RalGEFs), Ras or independent of Ras activation. Several other stimuli, known to be active in cancer cells, have been identified to activate Ral, including oxidative damage, hypoxia, calcium signaling, and androgen withdrawal. Once activated by exchange of GTP for GDP, Ral GTPases are able to associate physically with several known (and likely other uncharacterized) effector proteins, to mediate diverse cellular effects

14.2.6 CD24

CD24, is a glycosyl phosphatidyl inositol–linked surface protein [73], that has been identified as a downstream target of Ral signaling by profiling the expression of RalA/B–depleted bladder carcinoma cells [67, 68]. Originally identified as a surface differentiation marker of peripheral B-lymphocytes [73], CD24 received recent attention as a marker of stem cell populations of a variety of cancers [74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87]. CD24 overexpression has been associated with lung metastasis [88] as it promoted cancer cell rolling and adhesion to P-selectin in murine lung vasculature and platelets [76, 78, 79, 80, 85, 89, 90, 91, 92, 93, 94, 95]. Consistently, CD24 has been recently reported to be a hypoxia-regulated gene in some cancer cell lines [96, 97] that was down-regulated by Cox-2 inhibitor, Celecoxib, suggesting role in inflammation associated with metastasis [98, 99, 100]. CD24 is highly expressed in urothelial as well as other cancers. Immunohistological localization of CD24 revealed high levels of expression correlated with the stromal/muscle invasion, stage, grade and shorter patient disease-free survival [67, 101]. Depletion of CD24 function in bladder cancer cell lines was found to be associated with decreased cell proliferation and anchorage-independent growth, changes in the actin cytoskeleton, and induction of apoptosis [67]. In addition, monoclonal antibodies against CD24 that were efficacious in inhibiting in vitro and in vivo growth of colorectal and pancreatic cancer cells as well as sensitizing them to conventional adjuvant chemotherapeutics [98, 99, 100, 102, 103, 104], significantly reduced the number of lung metastases that developed after tail vein injection of the metastatic UMUC3 cell line in an experimental model of bladder cancer [105]. However, the exact mechanism of CD24 involvement in lung metastasis is still elusive.

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of UrologyPaul Mellon Urologic Cancer Institute, University of VirginiaCharlottesvilleUSA
  2. 2.Departments of Surgery and PharmacologyUniversity of Colorado Comprehensive Cancer CenterAuroraUSA

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