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1.  TAM macrophages promote growth and metastasis within the cancer ecosystem 
Oncoimmunology  2014;3(7):e941734.
Cancer continues to be the major cause of morbidity and death of more than 500,000 people in the US annually. Alternatively activated macrophages (M2 macrophages or TAMs) can facilitate tumor invasiveness and metastasis. As an invasive species in the tumor microenvironment, they provide an ideal therapeutic target.
PMCID: PMC4341447  PMID: 25954596
epithelial to mesenchymal transition; metastasis; prostate cancer; tumor associated macrophages
2.  The biology and treatment of oligometastatic cancer 
Oncotarget  2015;6(11):8491-8524.
Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, were noted on occasion historically and are now termed oligometastasis. The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e. if the primary cancer site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be achieved. Contemporary molecular diagnostics are edging closer to being able to determine where an individual metastatic deposit is within the continuum of malignancy. Preclinical models are on the outset of laying the groundwork for understanding the oligometastatic state. Meanwhile, in the clinic, patients are increasingly being designated as having oligometastatic disease and being treated owing to improved diagnostic imaging, novel treatment options with the potential to provide either direct or bridging therapy, and progressively broad definitions of oligometastasis.
PMCID: PMC4496163  PMID: 25940699
metastasis; therapy; tumor; spectrum theory; diaspora
3.  Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells 
Oncotarget  2014;6(1):130-143.
The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease.
PMCID: PMC4381583  PMID: 25426557
cytoskeleton; motility; cancer metabolism; glycolysis; metastasis
4.  The Cancer Diaspora: Metastasis beyond the seed and soil hypothesis 
Do cancer cells escape their confinement of their original habitat in the primary tumor or are they forced out by ecological changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, “diaspora” has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For example, ecological traps, habitats that lead to the extinction of a species, can be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy.
PMCID: PMC3835696  PMID: 24100626
5.  The Current State of Preclinical Prostate Cancer Animal Models 
The Prostate  2008;68(6):629-639.
Prostate cancer continues to be a major cause of morbidity and mortality in men around the world. The field of prostate cancer research continues to be hindered by the lack of relevant preclinical models to study tumorigenesis and to further development of effective prevention and therapeutic strategies. The Prostate Cancer Foundation held a Prostate Cancer Models Working Group (PCMWG) Summit on August 6th and 7th, 2007 to address these issues. The PCMWG reviewed the state of prostate cancer preclinical models and identified the current limitations of cell line, xenograft and genetically engineered mouse models that have hampered the transition of scientific findings from these models to human clinical trials. In addition the PCMWG identified administrative issues that inhibit the exchange of models and impede greater interactions between academic centers and these centers with industry. The PCMWG identified potential solutions for discovery bottlenecks that include: (1) insufficient number of models with insufficient molecular and biologic diversity to reflect human cancer, (2) a lack of understanding of the molecular events that define tumorigenesis, (3) a lack of tools for studying tumor–host interactions, (4) difficulty in accessing model systems across institutions, and (5) addressing why preclinical studies appear not to be predictive of human clinical trials. It should be possible to apply the knowledge gained molecular and epigenetic studies to develop new cell lines and models that mimic progressive and fatal prostate cancer and ultimately improve interventions.
PMCID: PMC3681409  PMID: 18213636
mouse; genetically engineered; cell lines
6.  Cross-species analysis of genome-wide regulatory networks identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy 
Cancer cell  2014;25(5):638-651.
To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth, by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer.
PMCID: PMC4051317  PMID: 24823640
7.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer 
Nature  2012;487(7406):239-243.
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2–4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS fusionnegative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumour growth. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.
PMCID: PMC3396711  PMID: 22722839
8.  Ecology meets cancer biology: The cancer swamp promotes the lethal cancer phenotype 
Oncotarget  2015;6(12):9669-9678.
As they grow, tumors fundamentally alter their microenvironment, disrupting the homeostasis of the host organ and eventually the patient as a whole. Lethality is the ultimate result of deregulated cell signaling and regulatory mechanisms as well as inappropriate host cell recruitment and activity that lead to the death of the patient. These processes have striking parallels to the framework of ecological biology: multiple interacting ecosystems (organ systems) within a larger biosphere (body), alterations in species stoichiometry (host cell types), resource cycling (cellular metabolism and cell-cell signaling), and ecosystem collapse (organ failure and death). In particular, as cancer cells generate their own niche within the tumor ecosystem, ecological engineering and autoeutrophication displace normal cell function and result in the creation of a hypoxic, acidic, and nutrient-poor environment. This “cancer swamp” has genetic and epigenetic effects at the local ecosystem level to promote metastasis and at the systemic host level to induce cytokine-mediated lethal syndromes, a major cause of death of cancer patients.
PMCID: PMC4496388  PMID: 25895024
ecosystem; autoeutrophication; selection; cancer hallmarks; lethal phenotype
9.  Integrated Multimodal Imaging of Dynamic Bone-Tumor Alterations Associated with Metastatic Prostate Cancer 
PLoS ONE  2015;10(4):e0123877.
Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease.
Trial Registration NCT02064283
PMCID: PMC4393258  PMID: 25859981
10.  Alternative CD44 splicing identifies epithelial prostate cancer cells from the mesenchymal counterparts 
An epithelial to mesenchymal transition (EMT) has been shown to be a necessary precursor to prostate cancer metastasis. Additionally, the differential expression and splicing of mRNAs has been identified as a key means to distinguish epithelial from mesenchymal cells by qPCR, western blotting and immunohistochemistry. However, few markers exist to differentiate between these cells by flow cytometry. We previously developed two cell lines, PC3-Epi (epithelial) and PC3-EMT (mesenchymal). RNAseq was used to determine the differential expression of membrane proteins on PC3-Epi/EMT. We used western blotting, qPCR and flow cytometry to validate the RNAseq results. CD44 was one of six membrane proteins found to be differentially spliced between epithelial and mesenchymal PC3 cells. Although total CD44 was positive in all PC3-Epi/EMT cells, PC3-Epi cells had a higher level of CD44v6 (CD44 variant exon 6). CD44v6 was able to differentiate epithelial from mesenchymal prostate cancer cells using either flow cytometry, western blotting or qPCR.
Electronic supplementary material
The online version of this article (doi:10.1007/s12032-015-0593-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4391735  PMID: 25850653
Epithelial to mesenchymal transition (EMT); CD44; OVOL1/2; ZEB1; E-cadherin (CDH1); RBM35A/ESRP1 epithelial splicing regulatory protein 1
11.  Characterization of bone metastases from rapid autopsies of prostate cancer patients 
Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research.
Experimental Design
We demonstrate, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 recent autopsies conducted at the University of Michigan, and analyzed the gene expression of these tissues using real time PCR and microarrays.
We present here the discovery of non-ossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to non-osseous metastases from the same patients
This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA and cDNA from tumor samples metastatic to the bone.
PMCID: PMC3117947  PMID: 21555375
Bone marrow; tumor; metastatic prostate cancer
12.  Frequent Discordance between ERG Gene Rearrangement and ERG Protein Expression in a Rapid Autopsy Cohort of Patients with Lethal, Metastatic, Castration-Resistant Prostate Cancer 
The Prostate  2014;74(12):1199-1208.
ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggests that ERG IHC may be less sensitive for ERG rearrangements in castration-resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC).
A tissue microarray (TMA) of tumor sites from these patients was evaluated for ERG, prostate specific antigen (PSA), and androgen receptor (AR) expression by IHC and correlated with ERG rearrangement status by fluorescent in situ hybridization (FISH). IHC was scored as the product of tumor cell staining intensity (0–3) and percentage of cells positive (0–100) (overall product score range = 0–300).
All sixteen (100%) ERG rearrangement negative (ERGneg) patients were also negative for ERG tumor cell expression (i.e., IHC product score = 0). Of the ten ERG rearrangement positive (ERGpos) patients, two (20%) were completely negative for ERG tumor cell expression, while eight (80%) had weak ERG expression (median IHC product score = 5–110). Of these eight ERGpos patients, five (63%) had at least one tumor site without any detectable ERG expression. For a given ERGpos patient, ERG expression varied both between and within tumor sites; AR and PSA expression also varied between tumor sites, and there was no significant correlation between ERG and AR or PSA expression.
These data reveal frequent discordance between ERG IHC and ERG FISH in ERGpos patients from this unique cohort of heavily-treated lethal mCRPC.
PMCID: PMC4156519  PMID: 25043157
TMPRSS2-ERG; androgen receptor (AR); immunohistochemistry (IHC); fluorescent in situ hybridization (FISH); rapid autopsy
13.  Inhibition of Prostate Cancer Bone Metastasis by Synthetic TF Antigen Mimic/Galectin-3 Inhibitor Lactulose-l-Leucine1 
Neoplasia (New York, N.Y.)  2012;14(1):65-73.
Currently incurable, prostate cancer metastasis has a remarkable ability to spread to the skeleton. Previous studies demonstrated that interactions mediated by the cancer-associated Thomsen-Friedenreich glycoantigen (TF-Ag) and the carbohydrate-binding protein galectin-3 play an important role in several rate-limiting steps of cancer metastasis such as metastatic cell adhesion to bone marrow endothelium, homotypic tumor cell aggregation, and clonogenic survival and growth. This study investigated the ability of a synthetic small-molecular-weight nontoxic carbohydrate-based TF-Ag mimic lactulose-l-leucine (Lac-l-Leu) to inhibit these processes in vitro and, ultimately, prostate cancer bone metastasis in vivo. Using an in vivo mouse model, based on intracardiac injection of human PC-3 prostate carcinoma cells stably expressing luciferase, we investigated the ability of Lac-l-Leu to impede the establishment and growth of bone metastasis. Parallel-flow chamber assay, homotypic aggregation assay, modified Boyden chamber assay, and clonogenic growth assay were used to assess the effects of Lac-l-Leu on tumor cell adhesion to the endothelium, homotypic tumor cell aggregation, transendothelial migration, and clonogenic survival and growth, respectively. We report that daily intraperitoneal administration of Lac-l-Leu resulted in a three-fold (P < .05) decrease in metastatic tumor burden compared with the untreated control. Mechanistically, the effect of Lac-l-Leu, which binds and inhibits galectins by mimicking essential structural features of the TF-Ag, was associated with a dose-dependent inhibition of prostate cancer cell adhesion to bone marrow endothelium, homotypic aggregation, transendothelial migration, and clonogenic growth. We conclude that small-molecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.
PMCID: PMC3281943  PMID: 22355275
14.  Successfully accelerating translational research at an academic medical center: The University of Michigan-Coulter Translational Research Partnership Program. 
Translational research encompasses the effective movement of new knowledge and discoveries into new approaches for prevention, diagnosis, and treatment of disease. There are many roadblocks to successful bench to bedside research, but few have received as much recent attention as the “valley of death”. The valley of death refers to the lack of funding and support for research that moves basic science discoveries into diagnostics, devices, and treatments in humans, and is ascribed to be the result of companies unwilling to fund research development that may not result in a drug or device that will be utilized in the clinic and conversely, the fact that researchers have no access to the funding needed to carry out preclinical and early clinical development to demonstrate potential efficacy in humans. The valley of death also exists because bridging the translational gap is dependent on successfully managing an additional four risks: Scientific, Intellectual Property, Market, and Regulatory. The University of Michigan (UM) has partnered with the Wallace H. Coulter Foundation (CF) to create a model providing an infrastructure to overcome these risks. This model is easily adoptable to other academic medical centers.
PMCID: PMC3075604  PMID: 21167009
16.  Multiple Roles of Chemokine (C-C Motif) Ligand 2 in Promoting Prostate Cancer Growth 
Prostate cancer continues to be the most common nonskin cancer diagnosed and the second leading cause of cancer death in men in the United States. Prostate cancer that has metastasized to bone remains incurable. The interactions between prostate cancer cells and the various cells of the host microenvironment result in enhanced growth of tumor cells and activation of host cells that together culminate in osteoblastic bone metastases. These dynamic tumor–host interactions are mediated by cancer and host-produced cytokines and chemokines. Among them, chemokine (C-C motif) ligand 2 (CCL2) has been identified as a prominent modulator of metastatic growth in the bone microenvironment. CCL2 is produced by bone marrow osteoblasts, endothelial cells, stromal cells, and prostate cancer cells. It has been demonstrated to modulate tumor-associated macrophage migration and promote osteoclast maturation. In addition, CCL2 functions through binding to its receptor CCR2 to induce prostate cell proliferation, migration, and invasion in both autocrine and paracrine manners. CCL2 protects prostate cancer cells from autophagic death by activating survivin through a PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B)–dependent mechanism. Inhibition of CCL2 substantially decreases macrophage infiltration, decreases osteoclast function, and inhibits prostate cancer growth in bone in preclinical animal models. The multiple roles of CCL2 in the tumor microenvironment make it an attractive therapeutic target in metastatic prostate cancer as well as in other cancers.
PMCID: PMC2857800  PMID: 20233997
17.  Classification of current anticancer immunotherapies 
Galluzzi, Lorenzo | Vacchelli, Erika | Pedro, José-Manuel Bravo-San | Buqué, Aitziber | Senovilla, Laura | Baracco, Elisa Elena | Bloy, Norma | Castoldi, Francesca | Abastado, Jean-Pierre | Agostinis, Patrizia | Apte, Ron N. | Aranda, Fernando | Ayyoub, Maha | Beckhove, Philipp | Blay, Jean-Yves | Bracci, Laura | Caignard, Anne | Castelli, Chiara | Cavallo, Federica | Celis, Estaban | Cerundolo, Vincenzo | Clayton, Aled | Colombo, Mario P. | Coussens, Lisa | Dhodapkar, Madhav V. | Eggermont, Alexander M. | Fearon, Douglas T. | Fridman, Wolf H. | Fučíková, Jitka | Gabrilovich, Dmitry I. | Galon, Jérôme | Garg, Abhishek | Ghiringhelli, François | Giaccone, Giuseppe | Gilboa, Eli | Gnjatic, Sacha | Hoos, Axel | Hosmalin, Anne | Jäger, Dirk | Kalinski, Pawel | Kärre, Klas | Kepp, Oliver | Kiessling, Rolf | Kirkwood, John M. | Klein, Eva | Knuth, Alexander | Lewis, Claire E. | Liblau, Roland | Lotze, Michael T. | Lugli, Enrico | Mach, Jean-Pierre | Mattei, Fabrizio | Mavilio, Domenico | Melero, Ignacio | Melief, Cornelis J. | Mittendorf, Elizabeth A. | Moretta, Lorenzo | Odunsi, Adekunke | Okada, Hideho | Palucka, Anna Karolina | Peter, Marcus E. | Pienta, Kenneth J. | Porgador, Angel | Prendergast, George C. | Rabinovich, Gabriel A. | Restifo, Nicholas P. | Rizvi, Naiyer | Sautès-Fridman, Catherine | Schreiber, Hans | Seliger, Barbara | Shiku, Hiroshi | Silva-Santos, Bruno | Smyth, Mark J. | Speiser, Daniel E. | Spisek, Radek | Srivastava, Pramod K. | Talmadge, James E. | Tartour, Eric | Van Der Burg, Sjoerd H. | Van Den Eynde, Benoît J. | Vile, Richard | Wagner, Hermann | Weber, Jeffrey S. | Whiteside, Theresa L. | Wolchok, Jedd D. | Zitvogel, Laurence | Zou, Weiping | Kroemer, Guido
Oncotarget  2014;5(24):12472-12508.
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
PMCID: PMC4350348  PMID: 25537519
adoptive cell transfer; checkpoint blockers; dendritic cell-based interventions; DNA-based vaccines; immunostimulatory cytokines; peptide-based vaccines; oncolytic viruses; Toll-like receptor agonists
18.  CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis 
CCL2 is a chemokine known to recruit monocytes and macrophages to sites of inflammation. A growing body of research suggests CCL2 is progressively overexpressed in tumor beds and may play a role in the clinical progression of solid tumors. Cancer cells derived from several solid tumor types demonstrate functional receptors for CCL2, suggesting this chemokine may achieve tumorigenicity through direct effects on malignant cells; however, a variety of normal host cells that co-exist with cancer in the tumor microenvironment also respond to CCL2. These cells include macrophages, osteoclasts, endothelial cells, T-lymphocytes, and myeloid-derived immune suppressor cells (MDSCs). CCL2 mediated interactions between normal and malignant cells in the tumor microenvironment and plays a multi-faceted role in tumor progression.
PMCID: PMC2857769  PMID: 20005149
CCL2; CCR2; tumorigenesis; metastasis; prostate cancer
19.  Axl as a mediator of cellular growth and survival 
Oncotarget  2014;5(19):8818-8852.
The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context.
PMCID: PMC4253401  PMID: 25344858
Axl; TAM receptors; Gas6; cancer; tyrosine kinase; proliferation; apoptosis; immune; migration; inhibitor
20.  Prostate cancer promotes CD11b positive cells to differentiate into osteoclasts 
Journal of cellular biochemistry  2009;106(4):563-569.
Bone is the preferred site of prostate cancer metastasis, contributing to the morbidity and mortality of this disease. A key step in the successful establishment of prostate cancer bone metastases is activation of osteoclasts with subsequent bone resorption causing the release of several growth factors from the bone matrix. CD11b+ cells in bone marrow are enriched for osteoclast precursors. Conditioned media from prostate cancer PC-3 cells induces CD11b+ cells from human peripheral blood to differentiate into functional osteoclasts with subsequent bone resorption. Analysis of PC-3 conditioned media revealed high amounts of IL-6 and IL-8. CD11b+ cells were cultured with M-CSF and RANKL, IL-6, IL-8 and CCL2, alone or in combination. All of these conditions induced osteoclast fusion, but cells cultured with M-CSF, IL-6, IL-8 and CCL2 were capable of limited bone resorption. Co-incubation with IL-6 and IL-8 and the RANK inhibitor, RANK-Fc, failed to inhibit osteoclast fusion and bone resorption, suggesting a potential RANKL-independent mechanism of functional osteoclast formation. This study demonstrates that functional osteoclasts can be derived from CD11b+ cells derived from human PBMCs. Prostate cancer cells secrete factors, including IL-6 and IL-8, that play an important role in osteoclast fusion by a RANKL-independent mechanism.
PMCID: PMC2776620  PMID: 19170075
Osteoclast; CD11b; Prostate Cancer; RANKL; IL-6; IL-8; CCL2
21.  The Chemokine CCL2 Increases Prostate Tumor Growth and Bone Metastasis through Macrophage and Osteoclast Recruitment1 
Neoplasia (New York, N.Y.)  2009;11(11):1235-1242.
CC chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein-1) has been demonstrated to recruit monocytes to tumor sites. Monocytes are capable of being differentiated into tumor-associated macrophages (TAMs) and osteoclasts (OCs). TAMs have been shown to promote tumor growth in several cancer types. Osteoclasts have also been known to play an important role in cancer bone metastasis. To investigate the effects of CCL2 on tumorigenesis and its potential effects on bone metastasis of human prostate cancer, CCL2 was overexpressed into a luciferase-tagged human prostate cancer cell line PC-3. In vitro, the conditioned medium of CCL2 overexpressing PC-3luc cells (PC-3lucCCL2) was a potent chemoattractant for mouse monocytes in comparison to a conditioned medium from PC-3lucMock. In addition, CCL2 overexpression increased the growth of transplanted xenografts and increased the accumulation of macrophages in vivo. In a tumor dissemination model, PC-3lucCCL2 enhanced the growth of bone metastasis, which was associated with more functional OCs. Neutralizing antibodies targeting both human and mouse CCL2 inhibited the growth of PC-3luc, which was accompanied by a decrease in macrophage recruitment to the tumor. These findings suggest that CCL2 increases tumor growth and bone metastasis through recruitment of macrophages and OCs to the tumor site.
PMCID: PMC2767225  PMID: 19881959
22.  Disrupting the Networks of Cancer 
Ecosystems are interactive systems involving communities of species and their abiotic environment. Tumors are ecosystems in which cancer cells act as invasive species interacting with native host cell species in an established microenvironment within the larger host biosphere. At its heart, to study ecology is to study interconnectedness. In ecologic science, an ecologic network is a representation of the biotic interactions in an ecosystem in which species (nodes) are connected by pairwise interactions (links). Ecologic networks and signaling network models have been used to describe and compare the structures of ecosystems. It has been shown that disruption of ecologic networks through the loss of species or disruption of interactions between them can lead to the destruction of the ecosystem. Often, the destruction of a single node or link is not enough to disrupt the entire ecosystem. The more complex the network and its interactions, the more difficult it is to cause the extinction of a species, especially without leveraging other aspects of the ecosystem. Similarly, successful treatment of cancer with a single agent is rarely enough to cure a patient without strategically modifying the support systems conducive to survival of cancer. Cancer cells and the ecologic systems they reside in can be viewed as a series of nested networks. The most effective new paradigms for treatment will be developed through application of scaled network disruption.
PMCID: PMC4154593  PMID: 22442061
23.  Critical transitions in a game theoretic model of tumour metabolism 
Interface Focus  2014;4(4):20140014.
Tumour proliferation is promoted by an intratumoral metabolic symbiosis in which lactate from stromal cells fuels energy generation in the oxygenated domain of the tumour. Furthermore, empirical data show that tumour cells adopt an intermediate metabolic state between lactate respiration and glycolysis. This study models the metabolic symbiosis in the tumour through the formalism of evolutionary game theory. Our game model of metabolic symbiosis in cancer considers two types of tumour cells, hypoxic and oxygenated, while glucose and lactate are considered as the two main sources of energy within the tumour. The model confirms the presence of multiple intermediate stable states and hybrid energy strategies in the tumour. It predicts that nonlinear interaction between two subpopulations leads to tumour metabolic critical transitions and that tumours can obtain different intermediate states between glycolysis and respiration which can be regulated by the genomic mutation rate. The model can apply in the epithelial–stromal metabolic decoupling therapy.
PMCID: PMC4071509  PMID: 25097747
tumour metabolism; game theory; Warburg effect; epithelial–stromal metabolic decoupling; metabolic symbiosis in cancer; lactate shuttle
24.  Ecological Therapy for Cancer: Defining Tumors Using an Ecosystem Paradigm Suggests New Opportunities for Novel Cancer Treatments1 
Translational Oncology  2008;1(4):158-164.
We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as “ecological therapy” for cancer.
PMCID: PMC2582164  PMID: 19043526
25.  The evolving biology and treatment of prostate cancer 
The Journal of Clinical Investigation  2007;117(9):2351-2361.
Since the effectiveness of androgen deprivation for treatment of advanced prostate cancer was first demonstrated, prevention strategies and medical therapies for prostate cancer have been based on understanding the biologic underpinnings of the disease. Prostate cancer treatment is one of the best examples of a systematic therapeutic approach to target not only the cancer cells themselves, but the microenvironment in which they are proliferating. As the population ages and prostate cancer prevalence increases, challenges remain in the diagnosis of clinically relevant prostate cancer as well as the management of the metastatic and androgen-independent metastatic disease states.
PMCID: PMC1952634  PMID: 17786228

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