1,721,203 research outputs found
Evolution of cooperation among tumor cells
No full textThe evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the issue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell???stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as byproduct mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.Author manuscript. Published in final edited form as: Proc Natl Acad Sci U S A. 2006 September 5; 103(36): 13474-13479.The final published version of this article is located at: www.pnas.org/cgi/doi/10.1073/pnas.0606053103NIH U56 CA113004; to David E. AxelrodR.A. was supported by National Science Foundation (NSF) Grant SES-0240852. D.E.A. was supported by NSF Grant IIS-0312953, National Institutes of Health (NIH) Grant U56 CA113004, and New Jersey Commission on Cancer Research Grant 1076-CCR-SO. K.J.P. is an American Cancer Society Clinical Research Professor and is supported by NIH Grants CA69568, CA102872, and CA093900.NIH CA69568; to Kenneth J. PientaNIH CA102872; to Kenneth J. PientaNIH CA093900; to Kenneth J. PientaNSF SES-0240852; to Robert AxelrodNJ Commission on Cancer Research 1076-CCR-SO; to David E. AxelrodAlso available in PubMed Central. PMCID: PMC155738
Succesful separation between benign prostatic hyperplasia and prostate cancer by measurement of free and complexed PSA
No full textProstate-specific antigen (PSA) is a serine protease belonging to the human glandular kallikrein gene family [1–3]. The expression of PSA is mainly androgen dependent, and the detection of very high expression levels is restricted to the prostate tissue, but extraprostatic production at much lower levels has been demonstrated in several other tissues such as normal and malignant breast epithelium, endometrium, and bulbourethral glands [4–10]. PSA is synthesized by the columnar epithelium in the glandular ducts and acini of the prostate, but not by any other cells in prostate tissue. It is secreted at high concentrations (0.2-5mg/mL) into seminal fluid [4–6,11]. PSA is synthesized as an inactive precursor [2,3,12]. Like other glandular kallikreins, the PSA-precursor is processed stepwise by release of a leader peptide followed by liberation of an activation peptide that results in conversion of the zymogen into enzymatically active PSA [12]. This process may occur in parallel with the secretory release from the prostate epithelium and most probably occurs prior to the ejaculatory mixing of secretions from the prostate, seminal vesicles, and epididymis, since PSA is active in ejaculates collected from subjects with defective seminal vesicles and deferent ducts [1]. The protease(s) responsible for processing of the PSA precursor have not been identified. The mature 237-amino-acid form of PSA is a single-chain serine protease with extensive structural similarity to the glandular kallikreins [1,12–14]. However, the substrate specificity is uniquely different from that of the trypsin-like glandular kallikreins and resembles that of chymotrypsin, since PSA catalyzes the hydrolysis of peptide bonds’ carboxy-terminal to residues of tyrosine and leucine [15–17]. Synthetic peptide substrates for chymotrypsin can be used to measure PSA activity, but they are hydrolyzed much less efficiently by PSA than by chymotrypsin and are therefore both nonspecific and insensitive in detecting PSA activity [16]
Ecological therapy for cancer: Defining tumors utilizing an ecosystem paradigm suggests new opportunities for novel cancer treatments
No full textWe 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
Cancer cells utilize lipid droplets to survive chemotherapeutic stress
Full text linkOver 30,000 men in the United States die from metastatic prostate cancer each year. Metastatic cancer remains incurable as cancer cells become resistant to all known therapies. Despite decades of research, the source of therapeutic resistance is still largely unknown.
It is recognized that lipid reprogramming has a direct link to therapy desensitization and assists with cancer survival and success. Cancer associated alterations in lipid metabolism include increased lipid droplets (LDs) and enhanced lipid mobilization. Lipid droplets have canonically been known as storage reservoirs but have also recently come to light as an organelle that circumvents toxic stress. Higher levels of lipid droplets are associated with higher tumor aggressiveness and chemotherapy resistance in cancer. Prostate cancer cells have previously shown the ability to increase their levels of lipid droplets under stress. Lipid droplets are central anti-lipotoxic organelles that control cellular lipotoxicity by sequestering toxic or damaged lipids into inert triglycerides, cholesterol esters, and acyl ceramides. Sequestration of free fatty acids and damaged lipids into lipid droplets allows for lower lipotoxicity and lower lipid peroxidation in cells and higher chances of survival and future proliferation.
To determine the importance of lipid droplets in cancer we used database searches, metabolomic profiling, lipidomic profiling, live cell imaging, TEM, western blotting, flow cytometry, IHC, and qPCR. We discovered that PLIN1 (an exclusive lipid droplet surface protein), and DGAT1 (an enzyme that catalyzes the conversion of DAG and fatty acyl CoA to TAG which is the main component of lipid droplets) are higher in prostate cancer patients with lower disease-free survival and higher Gleason score. This clinical data indicates that more aggressive prostate cancer is most likely associated with higher levels of lipid droplets.
Our in vitro research demonstrates that cancer cells that survive chemotherapy have a significantly elevated level of lipid droplets in tandem with significantly elevated levels of oxidative stress. The elevation of lipid droplets in tandem with oxidative stress is indicative of lipid droplets sequestering damaged lipids from higher oxidative stress levels. We also established that lipid droplets form in cancer cells as soon as chemotherapy is applied suggesting a crucial method for avoiding lipotoxicity, lipid peroxidation, and cell death. To target lipid droplets in cancer we utilized pharmacological or genetic knockdown methods. Both methods were successful in significantly lowering lipid droplets in cancer cells. This inhibition allowed cancer cells to be sensitized to chemotherapy and resulted in lower viability of these cells.
Overall, our research proposes lipid droplets as important organelles that sequester toxic or damage lipids to promote survival. This work emphasizes the need for a dual treatment option of chemotherapy and lipid droplet inhibitors to advance the field towards more effective treatments for patients
Inhibition of Cell Survival Pathways to Treat Advanced Prostate Cancer
No full textProstate cancer remains a leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients; however, ADT fails in nearly all cases resulting in androgen-insensitive (AI) disease. Often, this progression is the result of the dysregulation of pre-survival Bcl-2 family proteins. Inhibition of these pro-survival Bcl-2 family proteins, therefore, may be an effective strategy to delay the onset of androgen-insensitive disease. Gossypol, a small mlecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, was attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]. Thus, this study was undertaken to better understand the in vitro effects of androgen receptor (AR) activation and induction of apoptosis via pro-survival Bcl-2 family protein inhibition. VCaP cells treated with gossypol result in an increase in apoptosis and downregulation of most Bcl-2 family member proteins, both pro-survival and pro-apoptosis. Upon AR activation in combination with gossypol treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the prosence of gossypol, and AR stimulation rescues protein expression. Akt and XIAP increase survival and XIAP is able to inhibit caspase activation. These data suggest that combination therapy of gossypol and androgen deprivation therapy may further delay the onset of androgen insensitive disease, resulting in prolonged survival of prostate cancer patients.Master'sCollege of Arts and Sciences: BiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/117855/1/McGregor.pd
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Microfluidic Studies of Pulsatile CXCL12 Stimulation on Prostate Cancer Cells.
Full text linkThis project investigates effects of flow and CXC chemokine ligand-12, CXCL12 stimuli on prostate cancer PC3 cell adhesion and migration by using microfluidics. Prostate carcinoma (PCa) is the most frequently diagnosed cancer in men and the second leading cause of cancer death in American males. Bone metastasis, known to be exacerbated by CXC chemokine receptor 4 (CXCR4) signaling pathways, is a major cause of high morbidity and mortality rates.
Although inhibition of CXCR4 is known to modulate cancer metastasis in vivo, the detailed mechanisms are still ambiguous. In vitro studies are useful but lack many physiological features and may not reveal the full range of cancer cell behaviors. For example, the temporal patterns of CXCR4 stimulation by CXCL12 in vivo may be pulsatile rather than continuous as is the case in many in vitro studies. The pulsatile exposure to CXCL12 is expected due to pulsatile release, active degradation by proteases, scavenging by CXCR7 expressing cells, binding to extracellular matrix, and by presence of interstitial flows. Active scavenging by CXCR7 has been shown to be critical for cell directed sensing and polarizing toward CXCL12 stimuli in vivo further reinforcing the potentially important role of temporal patterns of stimulation. Pulsatile stimulation makes mechanistic sense also since CXCR4 is a G-protein coupled receptor (GPCR) and continuous stimulation would simply lead to receptor desensitization.
Experiments by microfluidics demonstrate that pulses of CXCL12 rather than continuous stimulation induce significantly enhanced directed migration of PC3 cells. And as expected, CXCR4 knockdown PC3 cells migrated with significantly lower speed and directionality under CXCL12 stimulation compared with normal PC3 cells. During the course of studying the effect of temporal patterns of CXCL12 stimulation it was unexpectedly discovered that PC3 cells showed significantly better adhesion and migration behavior under pulsatile flow than under steady flow even in the absence of chemical stimulation. The technology helps clarify some of the biophysical effect of CXCR4 that may be important for physiological function of malignant prostate cancer cells.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/63775/1/ykchung_1.pd
Cancer cells utilize lipid droplets to survive chemotherapeutic stress
No full textOver 30,000 men in the United States die from metastatic prostate cancer each year. Metastatic cancer remains incurable as cancer cells become resistant to all known therapies. Despite decades of research, the source of therapeutic resistance is still largely unknown.
It is recognized that lipid reprogramming has a direct link to therapy desensitization and assists with cancer survival and success. Cancer associated alterations in lipid metabolism include increased lipid droplets (LDs) and enhanced lipid mobilization. Lipid droplets have canonically been known as storage reservoirs but have also recently come to light as an organelle that circumvents toxic stress. Higher levels of lipid droplets are associated with higher tumor aggressiveness and chemotherapy resistance in cancer. Prostate cancer cells have previously shown the ability to increase their levels of lipid droplets under stress. Lipid droplets are central anti-lipotoxic organelles that control cellular lipotoxicity by sequestering toxic or damaged lipids into inert triglycerides, cholesterol esters, and acyl ceramides. Sequestration of free fatty acids and damaged lipids into lipid droplets allows for lower lipotoxicity and lower lipid peroxidation in cells and higher chances of survival and future proliferation.
To determine the importance of lipid droplets in cancer we used database searches, metabolomic profiling, lipidomic profiling, live cell imaging, TEM, western blotting, flow cytometry, IHC, and qPCR. We discovered that PLIN1 (an exclusive lipid droplet surface protein), and DGAT1 (an enzyme that catalyzes the conversion of DAG and fatty acyl CoA to TAG which is the main component of lipid droplets) are higher in prostate cancer patients with lower disease-free survival and higher Gleason score. This clinical data indicates that more aggressive prostate cancer is most likely associated with higher levels of lipid droplets.
Our in vitro research demonstrates that cancer cells that survive chemotherapy have a significantly elevated level of lipid droplets in tandem with significantly elevated levels of oxidative stress. The elevation of lipid droplets in tandem with oxidative stress is indicative of lipid droplets sequestering damaged lipids from higher oxidative stress levels. We also established that lipid droplets form in cancer cells as soon as chemotherapy is applied suggesting a crucial method for avoiding lipotoxicity, lipid peroxidation, and cell death. To target lipid droplets in cancer we utilized pharmacological or genetic knockdown methods. Both methods were successful in significantly lowering lipid droplets in cancer cells. This inhibition allowed cancer cells to be sensitized to chemotherapy and resulted in lower viability of these cells.
Overall, our research proposes lipid droplets as important organelles that sequester toxic or damage lipids to promote survival. This work emphasizes the need for a dual treatment option of chemotherapy and lipid droplet inhibitors to advance the field towards more effective treatments for patients
Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic
No full textEmerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in cancer progression. PACCs are enlarged endocycling cells with increased genomic content that arise in response to stress. Our correlative study of patients with prostate cancer revealed that PACC presence was predictive of future metastasis. Ergo, we hypothesized that PACCs are pro-metastatic.
Though research has delineated the steps of the metastatic cascade, the determinants of bone-specific metastasis have remained elusive. Applying critical concepts from foraging theory and movement ecology, we hypothesized that organotropism results from habitat selection by foraging cancer cells. Specifically, we posited that cancer cells only perform habitat selection when employing reversible motile foraging strategies. Importantly, our framework emphasized the importance of testing chemotaxis when studying metastasis. Upon in vitro investigation, we found PACCs exhibit increased capacity for environment-sensing and directional migration in chemotactic environments. These data indicate that PACCs are chemotactic and thus have increased metastatic potential, making them worthy of further in vivo analysis.
Rigorous evaluation of in vivo metastasis models requires rapid and reliable circulating tumor cell (CTC) and disseminated tumor cell (DTC) detection. We developed a flow cytometry-based method that enables swift and simultaneous comparison of CTCs and DTCs from single animals, enabling evaluation of multiple metastatic steps within one model system. This approach is reproducible, high-throughput, broadly applicable and highly adaptable to a range of scientific inquiries. Most important for the present work, it enables the recovery and PACC-state analysis of CTCs and DTCs, allowing for a rapid first look at the comparative metastatic competency of PACCs vs. nonPACCs. We used our technique to query the metastatic competency of PACCs in vivo. Across all models, the majority of CTCs and DTCs were in the PACC state. Additionally, in vivo colonization assays proved PACC populations can regain proliferative capacity at metastatic sites following dormancy. An exploratory return to in vitro mechanistic experimentation revealed a PACC-specific partial-Epithelial-to-Mesenchymal-Transition phenotype, a phenotype that supports our hypothesized reversible motile foraging framework. Altogether, our data point to a causative relationship between PACCs and increased metastatic risk, revealing a new approach through which to target metastatic disease
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