• Cachexia
• Cytokine
• Patient-derived cell line
• Scirrhous gastric cancer
• Whole exome sequence

• Cachexia/etiology
• Cachexia/pathology
• Cachexia/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/complications
• Animals
• Humans
• Mice, Nude
• Cell Line, Tumor
• Adenocarcinoma, Scirrhous/pathology
• Adenocarcinoma, Scirrhous/genetics
• Adenocarcinoma, Scirrhous/complications
• Interleukin-18/blood
• Interleukin-8/blood
• Mice
• Muscular Atrophy/etiology
• Male

• Animals
• Humans
• Cachexia/metabolism
• Cachexia/etiology
• Energy Metabolism
• Metabolic Diseases/etiology
• Metabolic Diseases/metabolism
• Neoplasms/complications
• Neoplasms/metabolism

• 949017 EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)

• Anorexia
• Appetite regulation
• GDF15
• GFRAL
• Metabolism
• Obesity

• Humans
• Growth Differentiation Factor 15/metabolism
• Growth Differentiation Factor 15/blood
• Animals
• Metabolic Diseases/metabolism
• Energy Metabolism/physiology
• Obesity/metabolism
• Anorexia/metabolism
• Appetite/physiology

• Anorexia
• Cachexia
• Cancer
• Cytokines
• Inflammation
• Survival analysis

• Humans
• Male
• Cachexia/etiology
• Female
• Middle Aged
• Anorexia/etiology
• Neoplasms/complications
• Inflammation/blood
• Cytokines/blood
• Aged
• Syndrome

• Ovol1/Ovol2
• epidermis
• epithelial-mesenchymal plasticity (EMP)
• immune
• metabolism

• DNA-Binding Proteins/genetics
• Epidermis/metabolism
• Skin/metabolism
• Transcription Factors/metabolism
• Epidermal Cells/metabolism

• R01 CA244519 NCI NIH HHS
• T32 AI060573 NIAID NIH HHS
• R01 AA029124 NIAAA NIH HHS
• R01 AR068074 NIAMS NIH HHS
• R01 GM123731 NIGMS NIH HHS
• R35 GM145307 NIGMS NIH HHS
• R01 CA259370 NCI NIH HHS
• U01 AR073159 NIAMS NIH HHS
• P30 AR075047 NIAMS NIH HHS
• HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

• Glycolysis
• anabolism
• anorexia
• cachexia
• catabolism
• gluconeogenesis

As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work.

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.

• Cytokines
• Depression
• Frailty
• HIV
• Stigma

• Affect/physiology
• Aged
• Aging/blood
• Aging/immunology
• Aging/physiology
• Comorbidity
• Cross-Sectional Studies
• Cytokines/blood
• Depression/blood
• Depression/ethnology
• Depression/immunology
• Depression/physiopathology
• Female
• Frailty/blood
• Frailty/epidemiology
• Frailty/immunology
• Frailty/physiopathology
• Functional Status
• HIV Infections/blood
• HIV Infections/epidemiology
• HIV Infections/immunology
• HIV Infections/physiopathology
• Humans
• Inflammation/blood
• Inflammation/epidemiology
• Inflammation/immunology
• Loneliness
• Male
• Middle Aged
• Social Stigma

• T32 AG049666 NIA NIH HHS
• K23 AG072960 NIA NIH HHS
• T32 AI007613 NIAID NIH HHS
• P30 AG022845 NIA NIH HHS
• UL1 TR002384 NCATS NIH HHS
• K99 CA245488 NCI NIH HHS
• UL1TR000457 NCATS NIH HHS
• UL1 TR000457 NCATS NIH HHS
• American Psychological Foundation
• MAC AIDS Fund
• New York Community Trust
• National Institute on Aging
• National Cancer Institute
• National Institute of Allergy and Infectious Diseases
• National Center For Advancing Translational Sciences

• cytokine expression
• immunohistochemical staining
• prostate cancer
• prostatic needle biopsy specimen

• GDF-15
• cancer
• cardiovascular disease
• mortality
• onco-cardiology

• Multimodality
• Multispecialty
• Unintended weight loss
• Unintentional weight loss

• pancreatic cancer

• NMR metabolomics
• autophagy
• electrophysiological properties
• skeletal muscle atrophy
• sphingosine 1-phosphate
• sphingosine 1-phosphate receptors
• tumor necrosis factor alpha

For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.

• adipogenesis
• brown adipocytes
• differentiation
• p53
• white adipocytes

• Cachexia
• Cancer
• Diaphragm
• PDAC
• PDX
• Transcriptome

• cytokines
• inflammation
• smoking
• tobacco
• tumor microenvironment
• wasting

• U54CA233396-01 NCI NIH HHS

In this paper, we present evidence in support of our hypothesis that the neuronal histaminergic system might be involved in cancer cachexia¹. To build our premise, we present the research and the reasonable inferences that can be drawn from it in a section by section approach starting from one of the key issues related to cachexia, increased resting energy expenditure (REE), and progressing to the other, anorexia. Based on an extensive survey of the literature and our own deliberations on the abovementioned topics, we investigate whether histamine signaling might be the mechanism used by a tumor to hijack the body's thermogenic machinery. Our hypothesis in short is that hypothalamic histaminergic neurons are stimulated by inputs from the parasympathetic nervous system (PSNS), which senses tumor traits early in cancer development. Histamine release in the preoptic area of the hypothalamus primarily activates brown adipose tissue (BAT), triggering a highly energy demanding mechanism. Chronic activation of BAT, which, in this context, refers to intermittent and/or low grade activation by the sympathetic nervous system, leads to browning of white adipose tissue and further enhances thermogenic potential. Aberrant histamine signaling not only triggers energy-consuming processes, but also anorexia. Moreover, since functions such as taste, smell, and sleep are governed by discrete structures of the brain, which are targeted by distinct histaminergic neuron populations even relatively minor symptoms of cachexia, such as sleep disturbances and taste and smell distortions, also might be ascribed to aberrant histamine signaling. In late stage cachexia, the sympathetic tone in skeletal muscle breaks down, which we hypothesize might be caused by a reduction in histamine signaling or by the interference of other cachexia related mechanisms. Histamine signaling thus might delineate distinct stages of cachexia progression, with the early phase marked by a PSNS-mediated increase in histamine signaling, increased sympathetic tone and symptomatic adipose tissue depletion, and the late phase characterized by reduced histamine signaling, decreased sympathetic tone and symptomatic muscle wasting. To support our hypothesis, we review the literature from across disciplines and highlight the many commonalities between the mechanisms underlying cancer cachexia and current research findings on the regulation of energy homeostasis (particularly as it relates to hypothalamic histamine signaling). Extrapolating from the current body of knowledge, we develop our hypothetical framework (based on experimentally falsifiable assumptions) about the role of a distinct neuron population in the pathophysiology of cancer cachexia. Our hope is that presenting our ideas will spark discussion about the pathophysiology of cachexia, cancer's devastating and intractable syndrome.

• anorexia
• cancer cachexia
• central histaminergic system
• energy expenditure
• food intake
• histamine signaling
• histaminergic neurons
• parasympathetic nervous system

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.

• cachexia
• interleukin-8
• muscle wasting

• cachexia
• inflammation
• mitochondria
• protein synthesis

• Anamorelin
• Appetite
• Cancer cachexia
• Food intake
• Phase I studies

• C2C12 cells
• Interleukin-8
• cachexia
• computed tomography
• secretome
• tumor-derived factor

• 17/21223-9 Fundação de Amparo à Pesquisa do Estado de São Paulo

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

• cachexia
• cytokines
• innate immune system
• pancreatic cancer

Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have been correlated with CC; however, its prognostic significance remains unclear. In this study, serum levels of the CC-related cytokines were determined in normal donors and PC patients. IL-8 expression was assessed in PC tissue microarrays. The correlation of levels of each cytokine with disease progression, weight loss, and sarcopenia was calculated. The relationships among the baseline variables, CC, and IL-8 expression with disease progression were examined using univariate and multivariate analyses. Of these mentioned cytokines, only serum IL-8 level was elevated in the locally advanced group (n = 55) compared with the normal (n = 17) and resected groups (n = 55). Serum IL-8 level was positively correlated with CC status, weight loss, sarcopenia, but was negatively correlated with total psoas area (TPA). IL-8 expression in tissue samples was also positively associated with weight loss. Furthermore, serum IL-8 level was an independent predictor of survival. In conclusion, elevated serum IL-8 level significantly correlates with CC and sarcopenia and can be used as a prognostic indicator in PC.

• IL-6
• IL-8
• cancer cachexia
• interleukin (IL)-1β
• pancreatic cancer
• sarcopenia
• tumor necrosis factor (TNF)-α

• cancer cachexia
• exosomes
• extracellular vesicles

Cachexia is a deadly muscle wasting syndrome that arises under conditions linked to chronic inflammation, such as cancer. Cytokines, including interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and their downstream effectors such as Signal Transducer and Activator of Transcription 3 (STAT3), have been shown to play a prominent role in muscle wasting. Previously, we demonstrated that Pateamine A (PatA), a compound that targets eukaryotic initiation factor 4A (eIF4A), could prevent muscle wasting by modulating the translation of the inducible Nitric Oxide Synthase (iNOS) mRNA. Here we show that hippuristanol, a compound that impedes eIF4A in a manner distinct from PatA, similarly inhibits the iNOS/NO pathway and cytokine-induced muscle wasting. Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3-gene targets such as IL-6. The decreased activation of STAT3, which resulted from a decrease in STAT3 protein expression, was due to the inhibition of STAT3 translation as there were no changes in STAT3 mRNA levels. These effects are likely dependent on the inhibition of eIF4A activity since we observed similar results using PatA. Our results identify the inhibition of eIF4A-responsive transcripts, such as STAT3, as a viable approach to alleviate cachexia.

Skeletal muscle atrophy, the most characteristic feature of cancer cachexia, often occurs in patients with cancer undergoing chemotherapy. Antrodia cinnamomea (AC) a widely used edible medical fungus, exhibits hepatoprotective, anti-inflammatory and anticancer activities. In this study, we investigated whether combined treatment with the ethonolic extract of AC ameliorates cachexia symptoms, especially muscle wasting, in lung tumor-bearing mice treated with chemotherapy. Our results revealed that gemcitabine and cisplatin-induced severe body weight loss and skeletal muscle atrophy in the mice with cancer were greatly attenuated after AC extract administration. The protection may be attributed to the inhibition of skeletal muscle proteolysis by suppressing myostatin and activin release, muscle wasting-related FoxO3/MuRF-1/MAFbx signaling, proteasomal enzyme activity, and pro-inflammatory cytokine production. A significant decrease in insulin-like growth factor 1 (IGF-1) expression and formation was observed in the atrophying muscle of the conventional chemotherapy treatment group (CGC), and this decrease was markedly reversed by AC treatment. Additionally, the anorexia, intestinal injury and dysfunction that occurred in the CGC group were mitigated by AC extract. Taken together, these results demonstrated that the AC extract has a protective effect against chemotherapy-induced muscle atrophy mainly by attenuating muscle proteolysis, pro-inflammatory cytokine production, and anorexia, and activating IGF-1-dependent protein synthesis.

• Antrodia cinnamomea
• cancer cachexia
• chemotherapy
• lung tumor
• muscle atrophy

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.

• biomarkers
• cancer therapy
• chemo treatment
• malnutrition
• nutritional intervention

• Biomarker
• Cancer cachexia
• Muscle atrophy

The regulation of food intake and body weight has been hotly investigated. In the present study, we show that stanniocalcin2 (STC2), a cytokine ubiquitously expressed and especially upregulated in many types of human cancers, has a regulatory role in food intake and weight loss. Systemic treatment of C57BL/6 mice with recombinant STC2 protein resulted in decreased food intake and body weight, whereas energy expenditure was not affected. Similarly, STC2 treatment also induced anorexia in hyperphagic leptin-deficient mice, leading to a significant reduction in body weight and improvement of blood glucose levels. Furthermore, intracerebroventricular administration of STC2 to mice led to an acute decrease in food intake, which was mediated, at least in part, by activation of STAT3 pathway. Taken together, our results revealed the importance of STC2 in the regulation of feeding behavior as well as body weight.

• STAT3
• appetite
• body weight
• stanniocalcin 2

Inflammasomes are multi-proteins complex regulating inflammation-associated signaling. While inflammation plays a critical role in cancer cell growth, studies remain uncharacterized on the role of inflammasomes in prostate cancer. Using Gene Expression Omnibus (GEO) public datasets, we screened the expression profiles of inflammasome sensors NLRP3, NLRC4, NLRP6, NRLP12, and AIM2 in prostate tumor tissues, and verified their mRNA level in a panel of prostate cancer cell lines. The selected expression of NLRP3 and NLRP12 inflammasomes was validated, and the clinical association was evaluated in human prostate archival tumor tissues. We observed that the expression of inflammasome sensors was dysregulated at the mRNA level except for the NLRP12. The intensity of NLRP12 immunostaining was significantly higher in malignant prostate as compared to their adjacent benign tissues. In contrast, the NLRP3 immunostaining in prostate tissues was heterogeneous. The inflammasome complex proteins ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1, as well as its downstream targets IL-1β and IL-18 were confined to aggressive prostate cancer cells. These data suggest an increased expression of NLRP12 in association with prostate cancer and support the role of NLRP12 inflammasome complex regulating inflammatory cytokines in understanding the role of inflammation in the prostate cancer.

The current study was designed to investigate the effect of crocetin on the proliferation inhibition of colon cancer cells and the underlying mechanism.

MTT assay showed inhibition of proliferation of colon cancer cells in a dose based manner by crocetin treatment. At 30 µM concentration of crocetin proliferation rate of colon cancer cells was reduced to 14% after 24 h. Flow cytometry and fluorescence microscopy revealed induction of apoptosis in colon cancer cells on treatment with crocetin. The tube formation was suppressed significantly in the cultures of HUVEC treated with 30 µM concentration of crocetin compared to the control cultures.

The results from transwell assay revealed a significant reduction in the population of DU-145 cells passing through filters of transwell on treatment with crocetin compared to the control cells. Treatment of the DU-145 cells with crocetin caused a significant reduction in the expression levels of NF-κB, VEGF and MMP-9. The results from RT-PCR analysis revealed a significant reduction in the expression of genes involved in inflammation including, HMGB1, IL-6 and IL-8 on treatment of DU-145 cells with crocetin. However, the expression of NAG-1 gene was increased by crocetin treatment in DU-145 cells significantly compared to the control cells.

Crocetin inhibits growth of colon cancer cells and prevents tube formation through induction of apoptosis. Therefore, crocetin can be used efficiently for the treatment of colon cancer.

• Inflammation
• Invasion
• Migration
• Transwell
• Tube

• angiogenesis
• cytokines
• interleukin-8
• metastasis
• nanotherapy

• Animals
• Biocompatible Materials
• Cell Line, Tumor
• Humans
• Interleukin-8/genetics
• Interleukin-8/metabolism
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Nude
• Nanoparticles/administration & dosage
• Nanoparticles/chemistry
• Neoplasm Metastasis
• Neovascularization, Pathologic/therapy
• Polyesters/chemistry
• Prostatic Neoplasms/therapy
• RNA, Small Interfering/genetics
• Tumor Burden/genetics
• Xenograft Model Antitumor Assays

• P30 CA016056 NCI NIH HHS
• R21 CA167177 NCI NIH HHS

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research.

A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically.

More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

• Chronic pancreatitis
• Cytokines
• Inflammation
• Pancreatic adenocarcinoma

• Accumulation
• Bioavailability
• Cancer
• Clearance
• Vascular remodeling

• Cytokine
• Disuse
• Hypogonadism
• Mitochondria

The complex interactions that occur between human tumors, tumor infiltrating lymphocytes (TIL) and the systemic immune system are likely to define critical factors in the host response to cancer. While conventional animal models have identified an array of potential anti-tumor therapies, mouse models often fail to translate into effective human treatments. Our goal is to establish a humanized tumor model as a more effective pre-clinical platform for understanding and manipulating TIL.

The immune system in NOD/SCID/IL-2Rγnull (NSG) mice was reconstituted by the co-administration of human peripheral blood lymphocytes (PBL) or subsets (CD4+ or CD8+) and autologous human dendritic cells (DC), and animals simultaneously challenged by implanting human prostate cancer cells (PC3 line). Tumor growth was evaluated over time and the phenotype of recovered splenocytes and TIL characterized by flow cytometry and immunohistochemistry (IHC). Serum levels of circulating cytokines and chemokines were also assessed.

A tumor-bearing huPBL-NSG model was established in which human leukocytes reconstituted secondary lymphoid organs and promoted the accumulation of TIL. These TIL exhibited a unique phenotype when compared to splenocytes with a predominance of CD8+ T cells that exhibited increased expression of CD69, CD56, and an effector memory phenotype. TIL from huPBL-NSG animals closely matched the features of TIL recovered from primary human prostate cancers. Human cytokines were readily detectible in the serum and exhibited a different profile in animals implanted with PBL alone, tumor alone, and those reconstituted with both. Immune reconstitution slowed but could not eliminate tumor growth and this effect required the presence of CD4+ T cell help.

Simultaneous implantation of human PBL, DC and tumor results in a huPBL-NSG model that recapitulates the development of human TIL and allows an assessment of tumor and immune system interaction that cannot be carried out in humans. Furthermore, the capacity to manipulate individual features and cell populations provides an opportunity for hypothesis testing and outcome monitoring in a humanized system that may be more relevant than conventional mouse models.

• Human prostate cancer
• Humanized
• NOD/SCID/IL-2Rγnull
• Tumor infiltrating lymphocyte

• epidemiology

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Asian People
• Bipolar Disorder/epidemiology
• Case-Control Studies
• Depressive Disorder/epidemiology
• Female
• Humans
• Male
• Middle Aged
• Multivariate Analysis
• Prostatic Neoplasms/epidemiology
• Regression Analysis
• Remission Induction
• Retrospective Studies
• Risk Factors
• Social Class
• Taiwan/epidemiology
• Young Adult

• ADC
• PSMA
• patient-derived xenografts
• prostate cancer

• Animals
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized
• Antigens, Surface/immunology
• Drug Delivery Systems
• Glutamate Carboxypeptidase II/immunology
• Immunoconjugates
• Male
• Mice
• Neoplasm Transplantation
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/immunology
• Prostatic Neoplasms/pathology
• Treatment Outcome
• Xenograft Model Antitumor Assays

• Cancer
• Cannabinoid receptors
• Endocannabinoids
• Inflammation
• Proliferation

• cachexia
• cancer
• head and neck
• indirect calorimetry
• metabolism

• Castration resistant prostate cancer
• interleukin-8
• prostate cancer
• prostate specific antigen
• serum biomarker
• tumor necrosis factor-α

In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer.