Stages Of Cancer Development Research Articles

Abstract SY26-01: Vaccine induced immunity against cancer genes to prevent and treat pancreatic cancer

Abstract Pancreatic cancer remains a “death sentence,” with the poorest survival rates reported for solid tumors. Escalating this problem is the fact that pancreatic cancer is among the most resistant cancers to traditional forms of therapy. But in this new era of targeted therapies, there is reason to hope that significant progress will be made in the development of new interventions for both treatment and prevention in the near future. In fact, we have entered into a new era of cancer therapies and are witnessing the rapid approval of antibodies and small molecule agents that inhibit cancer associated pathways. In the past few years we have also witnessed the approval of vaccines for cancer prevention (HPV vaccines, Gardasil, Cervarix) and cancer treatment (prostate cancer vaccine, Sipuleucel-T, Provenge); and the first immune modulating agent (Yervoy, Ipilimumab) that blocks the down regulatory signal, CTLA-4 on T cells, thereby enhancing immune activity against malignant melanoma. These groundbreaking examples have opened the floodgates for a whole new class of anticancer agents that harness the power of the immune system. Until recently, barriers to immunotherapy clinical successes for pancreatic cancer have been due to a lack of understanding of the immune pathways within the pancreatic tumor microenvironment that hinder successful immune responses even at the earliest stages of cancer development. Recent advances in our understanding of its immunobiology has identified new targets for developing cancer specific vaccines and new targets for modulating the tumor microenvironment to allow more potent activation and improved access of vaccine induced immune responses. We are just learning that non-neoplastic cells, including cancer-associated myofibroblasts, regulatory T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are hijacked by pre-invasive and invasive cancer cells to create a tolerogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this cancer supporting polarization within the tumor microenvironment with the goal of tipping the balance in favor of an anticancer immunity. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable and hopefully preventable disease. This presentation will provide new data supporting a role for targeting tumor initiating and metastasis supporting genes as immunotherapy for preventing tumor initiation and progression.

Heparanase cooperates with Ras to drive breast and skin tumorigenesis.

Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B.

As cellular models for in vitro liver cancer and toxicity studies, HepG2 and Hep3B are the two most frequently used liver cancer cell lines. Because of their similarities they are often treated as the same in experimental studies. However, there are many differences that have been largely over-sighted or ignored between them. In this review, we summarize the differences between HepG2 and Hep3B cell lines that can be found in the literature based on PubMed search. We particularly focus on the differential gene expression, differential drug responses (chemosensitivity, cell cycle and growth inhibition, and gene induction), signaling pathways associated with these differences, as well as the factors in governing these differences between HepG2 and Hep3B cell lines. Based on our analyses of the available data, we suggest that neither HBx nor p53 may be the crucial factor to determine the differences between HepG2 and Hep3B cell lines although HBx regulates the expression of the majority of genes that are differentially expressed between HepG2 and Hep3B. Instead, the different maturation stages in cancer development of the original specimen between HepG2 and Hep3B may be responsible for the differences between them. This review provides insight into the molecular mechanisms underlying the differences between HepG2 and Hep3B and help investigators especially the beginners in the areas of liver cancer research and drug metabolism to fully understand, and thus better use and interpret the data from these two cell lines in their studies.

SU‐E‐J‐03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

Purpose:The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors.Methods:Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes (211At, 213Bi, 223Ra and 225Ac) and 6 beta emitters (32P, 33P, 67Cu, 90Y, 131I and 177Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters.Results:We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors.Conclusion:The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency.

Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. Here we map acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause chronic inflammation that develops into cancer. In both human and mouse cancer genomes, we find few somatic point mutations with no impairment of cancer genes, but massive gene amplification and rearrangements. This genomic landscape differs from that of virus- and alcohol-associated liver cancer. Copy-number gains preferentially occur at late stages of cancer development and frequently target the MAPK signalling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retards cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be distinguished from those determined by other aetiological factors.

Nod-like receptors: key molecular switches in the conundrum of cancer.

It is believed the immune system can contribute to oncogenic transformation especially in settings of chronic inflammation, be activated during immunosurveillance to destroy early neoplastic cells before they undergo malignant outgrowth, and finally, can assist growth of established tumors by preventing clearance, remodeling surrounding tissue, and promoting metastatic events. These seemingly opposing roles of the immune system at the different stages of cancer development must all be mediated by innate signaling mechanisms that regulate the overall state of immune activation. Recently, the cytosolic nod-like receptor (NLR) pathway of innate immunity has gained a lot of attention in the tumor immunology field due to its known involvement in promoting inflammation and immunity, and conversely, in regulating tissue repair processes. In this review, we present all the current evidence for NLR involvement in the different stages of neoplasia to understand how a single molecular pathway can contribute to conflicting immunological interactions with cancer.

Prophylactic cancer vaccine, from concept to reality?

The demonstration that for infectious diseases vaccine-induced immunity is in principle only effective before rather than after infection occurs, provides valuable insights in understanding the nature of immune system and the challenges in cancer treatment. Besides the already known underlying counter-back mechanisms, the astronomical numbers of tumor cells in established tumors could overwhelm the limited amount of specific T cells induced by vaccination, which may account for the modest efficiency of immunotherapy against cancer. We speculate that the long window period for cancer development will allow immune-intervening strategies (e.g., the proper prophylactic vaccination) to promote adaptive mechanisms toward an enhanced immunosurveillance, which could effectively eradicate or at least control the few precancerous cells undergoing neoplastic transformation during early premalignant stages in cancer development, and protect the host from lethal tumor formation. It should be emphasized that the pre-cancer-associated antigens but not the tumor-associated antigens seem to be the suitable antigens for designing prophylactic cancer vaccines. In addition, an ideal prophylactic cancer vaccine may contain multiple pre-cancer-associated antigens, which will provide broad and effective immune protection in a heterogeneous human population. Finally, we demonstrated that placenta-derived gp96, which can be readily obtained in high amount for vaccination, has the ability to initiate antitumor T-cell immunity via association with multiple embryo-cancer antigens. Further understanding placental gp96 associated with carcinoembryonic antigen repertoires that orchestrate immune defense networks against cancer formation will allow to provide an effective prophylactic approach in cancer prevention.

Exploiting APC Function as a Novel Cancer Therapy

The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancers such as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lung cancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting in loss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper of tumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of the Wnt/β -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/β-catenin signaling such as apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cell migration. Given the vast cellular processes involving APC, the loss of these "normal" functions due to mutation can contribute to chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function including the reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APCmutant cells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments for patients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting both the Wnt-dependent and -independent functions of APC.

Nucleotide metabolism, oncogene-induced senescence and cancer

Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.

The role of centrosomes in cells and their potential contribution to carcinogenesis

The centrosomes are subcellular organelles composed of two centrioles surrounded by a pericentriolar material. In animal cells they are responsible for the organization of the interphase microtubule cytoskeleton including microtubule nucleation and elongation, their attachment and release. The centrosomes are also involved in the construction of the mitotic spindle and chromosome segregation. More than a century ago it was suggested that these structures might be involved in human diseases, including cancer. Cancer cells show a high frequency of centrosome aberrations, especially amplification. Centrosome defects may increase the incidence of multipolar mitoses that lead to chromosomal segregation abnormalities and aneuploidy, which is the predominant type of genomic instability found in human solid tumors. The number of these organelles in cells is strictly controlled and is dependent on the proper process of centrosome duplication. Multiple genes that are frequently found mutated in cancers encode proteins which participate in the regulation of centrosome duplication and the numeral integrity of centrosomes. In recent years there has been growing interest in the potential participation of centrosomes in the process of carcinogenesis, especially because centrosome abnormalities are observed in premalignant stages of cancer development. The common presence of abnormal centrosomes in cancer cells and the role these organelles play in the cells suggest that the factors controlling the number of centrosomes may be potential targets for cancer therapy.

Inflammasomes in cancer: a double-edged sword

Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent inducers of interleukin (IL)-1β and IL-18 during inflammation, are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific context. Here we summarize the role of different inflammasome complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro-inflammatory cytokines play in immunity.

Quantification of Viable Aerobic Bacteria in Oral Squamous Cell Carcinoma Tissue – A Microbiological Approach

Despite increasing interest in the possible relationships between bacteria and the different stages of cancer development, the association of bacteria with cancer of the oral cavity has yet to be adequately examined. With that in mind, the primary objective of our study was to determine microbiologically the presence of viable aerobic bacteria in the lesional tissue of diagnosed cases of oral squamous cell carcinoma & in apparently normal tissue atleast 5cm. away from the cancerous lesion and to determine presence of viable aerobic bacteria in normal tissue surgically removed from patients undergoing surgery for non-neoplastic & non-inflammed lesions and then to compare among them. Cancerous lesions were removed surgically, and resected OSCC specimens were harvested under aseptic conditions. The specimen was placed on a sterile surface & with a new blade for each cut a 1cm 3 specimen was removed without compromising the pathological margins. The specimen was further divided into upper level, middle level and lower level of the lesion. Whenever possible, a control specimen consisting of non-tumourous tissues harvested at least 5cm away from the primary lesion was also obtained. All subsequent handling of the specimens was carried out using aseptic technique on surfaces cleaned with phenolic disinfectant. Tissue specimens were placed in betadine for 3 mins to disinfect the surfaces of each. Subsequently, tissues are placed in multiple labeled bottles of PBS (phosphate- buffered saline) to encourage the removal of any bacteria on the tissue surface and stored in deep freezer. Successful surface decontamination of the specimens indicates that the bacteria detected were from within the tissue. Bacteria have been cultured from within oral squamous cell carcinoma tissue. The significance of these bacteria within the tumor warrants further study.

Collagen as a double-edged sword in tumor progression

It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.

Green Tea In Acute Myeloid Leukemia

IntroductionGreen tea (GT) is chemically characterized by the presence of large amounts of polyphenolic compounds. The beneficial effects of green tea are well known. A number of epidemiologic studies have linked consumption of green tea to decreased risk of cancer, in vitro and animal models have supported green tea's ability to inhibit the different stages of cancer development. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. The development and progression of the leukemic disease involve deregulation of cell death response resulting in failure of production of normal blood cells. Accordingly, the goal of this work was to identify the effects of oral green tea administration in a xenografted model of leukemia as well as in a 65-year old patient diagnosed with AML with myelodysplasia-related changes. Material and MethodsIn vivo: HL-60 cells were maintained in 10% of RPMI medium. The HL-60 xenotransplant was performed using immunodeficient mice (NOD.CB17-Prkdcscid/J lineage (Jackson Lab. USA), (n= 6). Mice were inoculated, subcutaneously, in the dorsal region, 1x107cells/mice. Every 7 days the tumor volumes were evaluated according to the following formula: tumor volume (mm3) = (length x width2)/2. The GT (Galena Pharmaceutical) treatment started after tumors reached 100 to 200 mm3, it was given every day by gavage at 100mg/Kg body weight (diluent: water solution). Control group received equal amounts vehicle solution. After 21 days, the mice were sacrificed, tumors were removed, minced and homogenized in protein extraction buffer or fixed in formalin immediately for immunohistochemistry with antibodies for detection of apoptosis, autophagy and cell cycle processes. Clinical protocol: We performed a pilot study with an elderly AML patient unfit to conventional chemotherapy due to comorbidities and personal desire. Our primary goal was to confirm the suppressive activity of GT against leukemic blasts. Our secondary objective was to analyse possible changes in her adaptive and innate immune system induced by GT. Capsules containing 500 mg of GT were supplied by the Galena pharmaceutical. The patient received 1 capsule (500mg) once per day during 3 months and was evaluated once every 4 weeks by physical examination and laboratory testing. ResultsIn vivo: A 42% reduction of the tumor volume was observed in mice treated for 21 days with GT treatment, compared to untreated animals. The main proteins related to the autophagy process were analyzed and we found increased expression of beclin-1 and class III PI3K, ATG5-ATG12 and ATG7. Immunohistochemistry analysis showed higher LC3I/II staining in mice treated with GT compared to control. Decreased Bcl2 expression, increased Bax expression and no modulation of BcL-xL levels was also detected by immunohistochemistry in treated animals. Caspase 3 staining was active in GT mice. GT induces cell cycle arrest in S phase, with reduction of cyclin A and CDk2 expression and increased p21 staining. We could not observe any significant difference in cyclin D, cyclin E, Cdk2, 4 and 6 expression. GT promoted pronounced phosphorylation of AKT, ERK1/2 and JNK. Clinical protocol: During GT treatment, the patient did not present any complication, including infections and bleeding. She remained as outpatient during all protocol period. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Omega-3 polyunsaturated Fatty acids as potential chemopreventive agent for gastrointestinal cancer.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), has been acknowledged as essential very long-chain fatty acids contributing to either achieving optimal health or protection against diseases, and even longevity. Recent high impact studies dealing with EPA and DHA have sparked a renewed interest in using n-3 PUFAs for cancer prevention and cancer treatment, for which n-3 PUFAs may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, and metastasis against various cancers. However, gastrointestinal cancers develop implicated with the close connection between inflammation and cancer and n-3 PUFAs especially imposed excellent actions of antiinflammation and antioxidation as well as their restorative actions. In detail, these beneficial lipids can restore or modify inflammation-associated lipid distorsion and alteration of lipid rafts. Although the chemopreventive effect of n-3 PUFAs has been studied in various experimental models, our understanding regarding the underlying mechanisms of n-3 PUFAs against GI cancer is still limited. In this review article, we described the in-detailed perspective and underlying mechanism of n-3 PUFAs application for GI cancers and added in vivo efficacy of n-3 PUFAs with Fat-1 transgenic mice experience. We suggest that future work should consider the n-6/n-3 FA ratio, combination treatment of other nutritions and alteration of lipid rafts to be a key element in experimental design and analysis.

TGF-β signaling pathways in cancers

TGF-β is a multifunctional cytokine involved in growth, cell differentiation and maintenanceof tissue homeostasis. In addition, TGF-β plays a key role in the pathogenesis of many diseases, including cancer. TGF-β-induced signaling pathways have either tumor-suppression or tumor-promoting effects in a cancer-type-specific and stage-dependent manner. TGF-β at an early stage of cancer development induces signaling pathways involved in inhibitionof cell proliferation, induction of differentiation, apoptosis or autophagy, suppression of angiogenesis and inflammation. At a later stage of disease, TGF-β exerts metastasis-promoting activity associated with epithelial-to-mesenchymal transition, modulation of cancer microenvironment and extracellular matrix components, inflammation and immune suppression. Furthermore, the TGF-β pathways play a pivotal role in the maintenance of stem cell-like properties of tumor cells. The pleiotropic action of TGF-β during tumorigenesis depends on interactions with different signaling pathways, including Hedgehog, WNT, PI3K--AKT, NOTCH, INF-γ, TNF-α, and RAS-ERK.

Expression of Betapapillomavirus Oncogenes Increases the Number of Keratinocytes with Stem Cell-Like Properties

Human papillomaviruses (HPV) of genus Betapapillomavirus (betaPV) are associated with nonmelanoma skin cancer development in epidermodysplasia verruciformis (EV) and immunosuppressed patients. Epidemiological and molecular studies suggest a carcinogenic activity of betaPV during early stages of cancer development. Since viral oncoproteins delay and perturb keratinocyte differentiation, they may have the capacity to either retain or confer a "stem cell-like" state on oncogene-expressing cells. The aim of this study was to determine (i) whether betaPV alters the expression of cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM), that have been associated with epithelial stemness, and (ii) whether this confers functional stem cell-like properties to human cutaneous keratinocytes. Fluorescence-activated cell sorter (FACS) analysis revealed an increase in the number of cells with high CD44 and EpCAM expression in keratinocyte cultures expressing HPV type 8 (HPV8) oncogenes E2, E6, and E7. Particularly through E7 expression, a distinct increase in clonogenicity and in the formation and size of tumor spheres was observed, accompanied by reduction of the epithelial differentiation marker Calgranulin B. These stem cell-like properties could be attributed to the pool of CD44(high) EpCAM(high) cells, which was increased within the E7 cultures of HPV5, -8, and -20. Enhanced EpCAM levels were present in organotypic skin cultures of primary keratinocytes expressing E7 of the oncogenic HPV types HPV5, -8, and -16 and in clinical samples from EV patients. In conclusion, our data show that betaPV may increase the number of stem cell-like cells present during early carcinogenesis and thus enable the persistence and accumulation of DNA damage necessary to generate malignant stem cells.

Omega-3 Polyunsaturated Fatty Acids and Cancer

While the anticancer effect of omega-3 polyunsaturated fatty acids (omega-3 fatty acids), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been the subject of intense study, our understanding regarding the underlying mechanisms of omega-3 fatty acids against cancer is still limited. Recent studies describing the cancer protective effect of EPA and DHA have sparked a renewed interest in using these fatty acids for cancer prevention and treatment. Here, we summarize the significance of omega- 3 fatty acids in the initiation and progression of cancer, and review the complex mechanisms by which EPA and DHA are thought to have anticancer activities during cancer development. It is concluded that omega-3 fatty acids may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, metastasis and epigenetic abnormalities that are crucial to the onset and progression of cancer.

WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone

Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.

Inflammasomes in cancer: a double-edged sword

Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent inducers of interleukin (IL)-1β and IL-18 during inflammation, are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific context. Here we summarize the role of different inflammasome complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro-inflammatory cytokines play in immunity.