Tpl2 induces castration resistant prostate cancer progression and metastasis

Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial–mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT‐related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.     

Role of MAP kinase in tumor progression and invasion

Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinase-induction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.     

转移消失蛋白在肿瘤发生发展中的作用

肿瘤转移消失蛋白(missing in metastasis, MIM)是一种新近发现的肌动蛋白结合蛋白,主要参与细胞骨架的重塑、信号转导及转录活化,与肿瘤的生长和侵袭密切相关.近年来,该蛋白在不同肿瘤中作用机制的研究受到广泛关注,有着广阔的研究前景.本文通过综述MIM蛋白与肿瘤发生发展的相关性,从而为MIM蛋白在肿瘤诊断和治疗中的应用提供理论基础及新的策略.     

A twist for survival and cancer progression

A major obstacle to the expansion of abnormal cells with significant proliferative potential is the induction of programmed cell death. Consequently, oncogene-driven hyperproliferation must be associated with apoptosis inhibition to allow malignant outgrowth. The oncogenic cooperation of N-Myc and Twist-1 in the development of neuroblastoma, the most common and deadly solid tumour of childhood, perfectly illustrates such a process. N-Myc promotes cell proliferation, whereas Twist-1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway. On the basis of numerous recent studies reporting its overexpression in a variety of human cancers, we discuss in this review the role of Twist-1 as a potent inhibitor of the cell safety programs engaged in response to an abnormal mitogenic activity.     

Role of nitric oxide in tumor progression: Lessons from experimental tumors

Nitric oxide (NO), a potent biological mediator, plays a key role in physiological as well as pathological processes, including inflammation and cancer. The role of NO in tumor biology remains incompletely understood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor cell survival and consequently their metastatic ability, a large body of clinical and experimental data suggest a promoting role of NO in tumor progression and metastasis. We suggest that tumor cells capable of very high levels of NO production die in vivo, and those producing or exposed to lower levels of NO, or capable of resisting NO-mediated injury undergo a clonal selection because of their survival advantage; they also utilize certain NO-mediated mechanisms for promotion of growth, invasion and metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor neovasculature, and (c) a suppression of host anti-tumor defense. In this review, we discuss these mechanisms on the basis of data derived from experimental models, in particular, a mouse mammary tumor model in which the expression of eNOS by tumor cells is positively correlated with invasive and metastatic abilities. Tumor-derived NO was shown to promote tumor cell invasiveness and angiogenesis. The invasion-stimulating effects of NO were due to an upregulation of matrix metalloproteases and a downregulation of their natural inhibitors. Treatment of tumor-bearing mice with NO-blocking agents reduced the growth and vascularity of primary tumors and their spontaneous metastases. We propose that selected NO-blocking drugs may be useful in treating certain human cancers either as single agents or as a part of combination therapies.     

EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression

Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo. EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6-regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP.     

Heme oxygenase-1 in macrophages controls prostate cancer progression

Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.     

Role of diet in prostate cancer development and progression.

Increasing evidence supports the important role of nutrition in cancer prevention, including prevention of prostate cancer. In this review, we summarize data for some of the most consistently observed dietary associations for prostate cancer incidence, briefly consider possible postdiagnostic effects of nutrition on prostate cancer progression/survival, discuss new but limited data on diet-gene interactions, and comment on current areas of controversy for future research focus. Potential protective dietary elements include tomatoes/lycopene, other carotenoids, cruciferous vegetables, vitamin E, selenium, fish/marine omega-3 fatty acids, soy, isoflavones and polyphenols; whereas milk, dairy, calcium, zinc at high doses, saturated fat, grilled meats, and heterocyclic amines may increase risk. It is important to note that randomized clinical trial data exist only for vitamin E, calcium, beta-carotene, and selenium (all of which suggest inverse or no association). Several genes, such as MnSOD, XRCC1, and GST, may modify the association of specific nutrients and foods with prostate cancer risk; and further research is warranted to confirm these initial observed relationships. Until further clinical trial data are available on specific supplements and prostate cancer prevention, it would be prudent to emphasize a diet consisting of a wide variety of plant-based foods and fish; this is similar to what is recommended (and what is more well established) for the primary prevention of heart disease.     

DKC1 overexpression associated with prostate cancer progression

Background:

Dyskerin encoded by the DKC1 gene is a predominantly nucleolar protein essential for the formation of pseudouridine in RNA and the telomerase RNA subunit hTR. Inherited mutations inactivating dyskerin cause dyskeratosis congenita, a syndrome with progeroid features characterised by skin defects and haematopoiesis failure, as well as cancer susceptibility. In this study, we report DKC1 overexpression in prostate cancers.

Methods:

Expression of DKC1 was measured by quantitative RT–PCR in prostate cancer tissues in relation to hTR and the proliferation marker MKI67. Effects of dyskerin downregulation on proliferation, apoptosis and senescence of prostate cancer cell lines were determined.

Results:

DKC1 was significantly overexpressed in prostate cancers, particularly in high-stage and recurring cases, correlating moderately with hTR and MKI67. Dyskerin downregulation in prostate carcinoma cell lines by siRNA diminished cell proliferation, but elicited neither apoptosis nor senescence. Apoptosis induction by TNF-α or tunicamycin was not enhanced. Long-term downregulation led predominantly to cell shrinking and loss of adhesion.

Interpretation:

DKC1 upregulation in prostate cancers is common and likely to be necessary for extensive tumour growth. The phenotype of prostate carcinoma cell lines after dyskerin downregulation suggests that its most critical function is sustaining protein biosynthesis. Intriguingly, compromised function and overexpression of dyskerin can both contribute to cancer development.     

Steps in prostate cancer progression that lead to bone metastasis

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone are not completely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bidirectional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases.     

Steroid hormones stimulate human prostate cancer progression and metastasis

Tissue recombinants (TRs) composed of mouse urogenital mesenchyme (mUGM) plus an immortalized nontumorigenic human prostatic epithelial cell line (BPH-1) were grown under the kidney capsule of male athymic nude mice under different hormonal conditions. The objectives were to determine temporal plasma concentrations of testosterone (T) and estradiol-17beta (E2) that elicit progression of nontumorigenic human prostatic epithelial cells in vivo. Second, to determine whether mUGM+BPH-1 TRs in [T+E2]-treated hosts could progress to metastases. Control mouse hosts received no exogenous hormonal support, whereas treated mice received Silastic implants containing T and E2 for 1-4 months. Plasma from hormonally treated mice contained significantly higher (p < 0.01) concentrations of T at 1 month (11.7 vs. 0.9 ng/ml). Plasma levels of E2 in steroid implanted mice were significantly higher (p < 0.05) at 2 months (104.5 vs. 25.6 ng/l) and 4 months (122.8 vs. 19.2 pg/ml). Wet weights of mUGM+BPH-1 TRs from [T+E2]-implanted mice were significantly larger (p < 0.001) than those from untreated hosts. Untreated mUGM+BPH-1 TRs contained a well organized differentiated epithelium surrounded by smooth muscle stroma similar to developing prostate. In [T+E2]-implanted mice, mUGM+BPH-1 TRs formed carcinomas that contained a fibrous connective tissue stroma permeating the tumor; smooth muscle when present was associated with vasculature. Renal lymph nodes collected from [T+E2]-treated mice, but not untreated mice, contained metastatic carcinoma cells. Moreover, metastases could be observed at distant sites including lung and liver. Epithelial cells isolated from untreated mUGM+BPH-1 TRs exhibited benign histology and formed small nontumorigenic grafts when subsequently transplanted into athymic nude mice. In contrast, epithelial cells isolated from mUGM+BPH-1 tumors of [T+E2]-treated hosts formed large tumors that grew independent of stromal and hormonal support and developed lymph node metastases. We conclude that [T+E2]-treatment promotes prostatic cancer progression in mUGM+BPH-1 TRs. Use of mUGM in this system will allow future studies to utilize the power of mouse genetics to identify paracrine factors involved in human prostatic carcinogenesis.     

c-FOS suppresses ovarian cancer progression by changing adhesion

Background:

C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown.

Methods:

Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis.

Results:

Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis.

Conclusion:

In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces.     

Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression

Macrophages are an essential component of antitumor activity; however, the role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM-CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM-CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM-CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan-, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.     

Role of osteopontin in tumour progression

Since its first identification as a transformation-associated protein, osteopontin (OPN) has been recognised as important in the processes of tumorigenicity and metastasis. Here, we review the evidence that OPN might be considered as a candidate prognostic marker in human cancer. In animal systems, evidence from cell injection experiments and genetically manipulated mice suggest an important but complex role for the protein in tumour progression. Moreover, studies in a variety of human cancers associate high levels of OPN expression in tumours or in blood with more advanced cancers. The mechanism of action of OPN in promoting cancer is still unclear, and we consider aspects of OPN biology that can complicate interpretation of human studies. Nevertheless, growing evidence supports a role for OPN as a potential prognostic factor for various human cancers.     

Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15‐lipoxygenase‐2 in prostate cancer

The enzyme 15‐lipoxygenase‐2 (15‐LOX‐2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)‐hydroxyeicosatetraenoic acid. Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15‐LOX‐2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15‐LOX‐2 in prostate cancer, we expressed 15‐LOX‐2 as a fusion protein with GFP in DU145 and PC‐3 cells and found that 15‐LOX‐2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15‐LOX‐2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15‐LOX‐2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15‐LOX‐2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF‐A) was significantly reduced in prostate cancer cells with 15‐LOX‐2 expression restored. Our studies suggest that 15‐LOX‐2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15‐LOX‐2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo. © 2008 Wiley‐Liss, Inc.     

CD151 and prostate cancer progression: A review of current literature

Prostate cancer morbidity and mortality are increasing globally and in China, and the rate of metastasis is also rising, limiting the therapeutic effect and clinical prognosis of prostate cancer. CD151 is considered to be the first promoter of tumor metastasis in the tetraspanin superfamily. Previous research has linked CD151 to the progression of a number of malignancies, including prostate cancer. However, a recent study found that CD151 can inhibit the progression of prostate cancer. As a result, this paper examines existing research on CD151 and prostate cancer progression in order to clarify the relationship and provide a possible reference for future studies.     

The urokinase-type plasminogen activator system in prostate cancer metastasis

Accumulated clinical and experimental evidence indicates that the urokinase-type plasminogen activator (uPA) and its regulators are causatively involved in the metastatic phenotype of many types of cancers. In the past couple of decades, investigation on the role of the uPA system in human prostate cancer (PC) has been intensified and has yielded valuable insights. This review summarizes recent advances made in several areas regarding the clinical relevance, the function and the molecular mechanisms of the uPA system in PC metastasis. A current consensus suggests that the uPA system promotes PC metastasis by mediating pericellular plasminogen activation. Towards the development of therapeutic strategies that specifically target uPA-mediated PC metastasis, several remaining issues are discussed.