Including Blood Vasculature into a Game-Theoretic Model of Cancer Dynamics

For cancer, we develop a 2-D agent-based continuous-space game-theoretical model that considers cancer cells’ proximity to a blood vessel. Based on castrate resistant metastatic prostate cancer (mCRPC), the model considers the density and frequency (eco-evolutionary) dynamics of three cancer cell types: those that require exogenous testosterone ( T + ), those producing testosterone ( T P ), and those independent of testosterone ( T - ). We model proximity to a blood vessel by imagining four zones around the vessel. Zone 0 is the blood vessel. As rings, zones 1–3 are successively farther from the blood vessel and have successively lower carrying capacities. Zone 4 represents the space too far from the blood vessel and too poor in nutrients for cancer cell proliferation. Within the other three zones that are closer to the blood vessel, the cells’ proliferation probabilities are determined by zone-specific payoff matrices. We analyzed how zone width, dispersal, interactions across zone boundaries, and blood vessel dynamics influence the eco-evolutionary dynamics of cell types within zones and across the entire cancer cell population. At equilibrium, zone 3’s composition deviates from its evolutionary stable strategy (ESS) towards that of zone 2. Zone 2 sees deviations from its ESS because of dispersal from zones 1 and 3; however, its composition begins to resemble zone 1’s more so than zone 3’s. Frequency-dependent interactions between cells across zone boundaries have little effect on zone 2’s and zone 3’s composition but have decisive effects on zone 1. The composition of zone 1 diverges dramatically from both its own ESS, but also that of zone 2. That is because T + cells (highest frequency in zone 1) benefit from interacting with T P cells (highest frequency in zone 2). Zone 1 T + cells interacting with cells in zone 2 experience a higher likelihood of encountering a T P cell than when restricted to their own zone. As expected, increasing the width of zones decreases these impacts of cross-boundary dispersal and interactions. Increasing zone widths increases the persistence likelihood of the cancer subpopulation in the face of blood vessel dynamics, where the vessel may die or become occluded resulting in the “birth” of another blood vessel elsewhere in the space. With small zone widths, the cancer cell subpopulations cannot persist. With large zone widths, blood vessel dynamics create cancer cell subpopulations that resemble the ESS of zone 3 as the larger area of zone 3 and its contribution to cells within the necrotic zone 4 mean that zones 3 and 4 provide the likeliest colonizers for the new blood vessel. In conclusion, our model provides an alternative modeling approach for considering density-dependent, frequency-dependent, and dispersal dynamics into cancer models with spatial gradients around blood vessels. Additionally, our model can consider the occurrence of circulating tumor cells (cells that disperse into the blood vessel from zone 1) and the presence of live cancer cells within the necrotic regions of a tumor.

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Inherent CD40L Expression Complements CD8+ T Cell Dependent Anti-Tumor Immunity

Blood ◽

10.1182/blood.v122.21.4494.4494 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4494-4494

Author(s):

Andreas Thiel ◽

Marco Frentsch ◽

Regina Stark ◽

Alberto Sada Japp ◽

Joanna Listopad ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Cells ◽

Cancer Cell ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Cell Types ◽

Cd8 T Cell ◽

Novel Treatment ◽

Cd40l Expression

Introduction & Objective Adoptive T cell therapy with tumor-specific CD8+ T cells is a promising treatment option for a variety of malignant diseases. However, it is unclear which subset of CD8+ T cells characterized by distinct functions is most suitable for achieving effective and durable anti tumor responses. So far CD8+ T cells have been considered to act predominantly as cytotoxic effector cells in cellular anti-tumor immunity. In this respect cytolytic molecules such as perforin and granzymes and apoptosis-inducing receptors of the tumor necrosis family such as FasL, TNFα and TRAIL have been regarded as major CD8+ T cell effector mechanisms. Methods & Results We here demonstrate in an experimental tumor model that CD40L, the key molecule for “immunological help”, is expressed by up to 50% of tumor-specific CD8+ T cells in B6 mice challenged with SV40 T antigen+ cancer cells. To study the influence of CD40L on anti-tumor CD8+ T cell immunity in vivo we challenged Rag1-/- mice with cancer cells and transferred wt or CD40L-/- CD8+ T cells. Transfer of wt CD8+ T cells prevented the establishment of a solid tumor, whereas injection of CD40L-/- CD8+ T cells alone or in addition with wt CD4+ T cells resulted in a non-controlled tumor development similar to non-treated tumors. The requirement of CD40L on CD8+ T cells for tumor rejection was further confirmed by injecting cancer cells in mice that lack CD40L expression only on mature CD8+ T cells. CD40Lflox x E8Icre mice were more susceptible to tumor formation than wt mice. Furthermore we demonstrated that CD8+ T-cell derived CD40L had to interact with CD40 on cancer cells, an eminent signal to induce apoptosis in various cancer cell types. Conclusion Our results reveal a crucial functional relevance of CD40L expressed by CD8+ T cells in anti-tumor immunity. Various cancer cell types express CD40 and its engagement induces pro-apoptotic or growth-inhibitory signals in a variety of cancer cells. Therefore CD40 agonists are recognized as promising agents for therapeutic interventions. We here introduce CD40L+ CD8+ memory T cells as a new major physiological source of CD40L, essential for rejection of tumors. Our data reveal that the presence or absence of CD40L+ CD8+ T cells represents a crucial element in control of CD40 expressing cancers disclosing novel treatment approaches in adoptive T-cell therapies novel treatment approaches. Disclosures: No relevant conflicts of interest to declare.

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600 In vitro anticancer and immunomodulatory activities of NBT-167, a dimer of resveratrol

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0600 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A635-A635

Author(s):

Jeffrey Zhang ◽

Everett Henry ◽

L Harris Zhang ◽

Wanying Zhang

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Cells ◽

Cancer Cell ◽

Immune Cells ◽

Cell Killing ◽

Gamma Delta T Cells ◽

Gamma Delta ◽

Raw264.7 Macrophages

BackgroundResveratrol (3,4’,5-trihydroxystilbene), a stilbenoid isolated from many species of plants, is widely known for its antioxidative, anti-inflammatory, immunomodulatory and anticancer activities. Recently, novel resveratrol oligomers have been isolated from various plants; their diverse structures are characterized by the polymerization of two or more resveratrol units. Little is known regarding the anticancer and immunomodulating activities of these oligomers. In this study, we designed in vitro models to compare resveratrol side by side with its natural dimer NBT-167 for their anticancer and immunological activities.MethodsWe isolated resveratrol and its dimer (NBT-167) from plants. The potency of the compounds was compared side by side using cancer cell survival assays and immunological assays with various types of human cells including cancer cell lines, PBMCs and enriched NK, gamma delta T cells, THP-1 monocytic cells, HL-60 promyelocytic leukemia cells as well as mouse RAW264.7 macrophages.ResultsNBT-167 was found to be more potent than resveratrol in inhibiting growth of various cancer cells and modulation of cytokine production from anti-IgM, LPS, PHA or SEB stimulated PBMC. Both compounds similarly enhanced IL-2 stimulated NK and gamma delta T cell killing activity against K562 cells and modulated nitric oxide production from LPS/IFN-g induced RAW264.7 macrophages and phagocytotic activity of HL-60 cells. NBT-167 was slightly more potently than resveratrol in inhibiting chemotaxis of HL-60 cells and blocking cell cycle of THP-1 and HL-60 cells at G1/S transition. In addition, NBT-167, but not resveratrol, could increase IL-2 production and T cell proliferation stimulated with anti-CD3 and anti-CD28 and synergize with anti-PD-1 antibody to increase IL-2 and IFN-gamma production in co-culture of allotypic T cells and dendric cells (MLR).ConclusionsOur data showed that NBT-167, a dimer of resveratrol, had anticancer and immunomodulatory activities such as modulation of expression of cytokines in immune cells and induction of cancer cell-killing activities of NK and gamma delta T cells. Generally, NBT-167 appeared to have higher activities than resveratrol in modulating immune cells and inhibiting cancer cells. NBT-167 could be a promising cancer immunotherapeutic agent targeting both cancer cells and immune cells.

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Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

Scientific Reports ◽

10.1038/s41598-019-55145-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Matthew Tegowski ◽

Cheng Fan ◽

Albert S. Baldwin

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Cell Types ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Self Renewal ◽

Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

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Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/980658 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Claudia Torricelli ◽

Sara Salvadori ◽

Giuseppe Valacchi ◽

Karel Souček ◽

Eva Slabáková ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Electron Microscopic Examination ◽

Cell Types ◽

Beclin 1 ◽

Electron Microscopic ◽

Alternative Pathways ◽

Light Fluorescence ◽

Mcf 7

Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein. The contribution of autophagy and apoptosis to the cytotoxic effects of Rottlerin was examined by light, fluorescence, and electron microscopic examination and by western blotting analysis of apoptotic and autophagic markers. By comparing caspases-3-deficient (MCF-73def) and caspases-3-transfected MCF-7 cells (MCF-73trans), we found that Rottlerin induced a noncanonical, Bcl-2-, Beclin 1-, Akt-, and ERK-independent autophagic death in the former- and the caspases-mediated apoptosis in the latter, in not starved conditions and in the absence of any other treatment. These findings suggest that Rottlerin could be cytotoxic for different cancer cell types, both apoptosis competent and apoptosis resistant.

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T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Cells ◽

10.3390/cells9071588 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1588 ◽

Cited By ~ 3

Author(s):

Michael D. Crowther ◽

Inge Marie Svane ◽

Özcan Met

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Cells ◽

Cell Types ◽

Tumour Microenvironment ◽

Antigen Receptors ◽

The Road ◽

Multiple Cell ◽

On The Road ◽

Cell Gene

T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.

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Superoxide Dismutase 1 Regulation of CXCR4-Mediated Signaling in Prostate Cancer Cells is Dependent on Cellular Oxidative State

Cellular Physiology and Biochemistry ◽

10.1159/000438566 ◽

2015 ◽

Vol 37 (6) ◽

pp. 2071-2084 ◽

Cited By ~ 6

Author(s):

Brent Young ◽

Chad Purcell ◽

Yi-Qun Kuang ◽

Nicholle Charette ◽

Denis J. Dupré

Keyword(s):

Prostate Cancer ◽

Superoxide Dismutase ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Metastasis ◽

Direct Interaction ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Cell Types ◽

Intracellular Loop

Background/Aims: CXCL12, acting via one of its G protein-coupled receptors, CXCR4, is a chemoattractant for a broad range of cell types, including several types of cancer cells. Elevated expression of CXCR4, and its ligand CXCL12, play important roles in promoting cancer metastasis. Cancer cells have the potential for rapid and unlimited growth in an area that may have restricted blood supply, as oxidative stress is a common feature of solid tumors. Recent studies have reported that enhanced expression of cytosolic superoxide dismutase (SOD1), a critical enzyme responsible for regulation of superoxide radicals, may increase the aggressive and invasive potential of malignant cells in some cancers. Methods: We used a variety of biochemical approaches and a prostate cancer cell line to study the effects of SOD1 on CXCR4 signaling. Results: Here, we report a direct interaction between SOD1 and CXCR4. We showed that SOD1 interacts directly with the first intracellular loop (ICL1) of CXCR4 and that the CXCL12/CXCR4-mediated regulation of AKT activation, apoptosis and cell migration in prostate cancer (PCa) cells is differentially modulated under normal versus hypoxic conditions when SOD1 is present. Conclusions: This study highlights a potential new regulatory mechanism by which a sensor of the oxidative environment could directly regulate signal transduction of a receptor involved in cancer cell survival and migration.

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The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model

Cancers ◽

10.3390/cancers11121931 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1931 ◽

Cited By ~ 4

Author(s):

Roberta Armignacco ◽

Giulia Cantini ◽

Giada Poli ◽

Daniele Guasti ◽

Gabriella Nesi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Cell ◽

Adrenocortical Carcinoma ◽

Cancer Cell Line ◽

Cell Types ◽

Adrenocortical Cancer ◽

Solid Malignancies ◽

H295r Cells

Metabolic interplay between the tumor microenvironment and cancer cells is a potential target for novel anti-cancer approaches. Among stromal components, adipocytes and adipose precursors have been shown to actively participate in tumor progression in several solid malignancies. In adrenocortical carcinoma (ACC), a rare endocrine neoplasia with a poor prognosis, cancer cells often infiltrate the fat mass surrounding the adrenal organ, enabling possible crosstalk with the adipose cells. Here, by using an in vitro co-culture system, we show that the interaction between adipose-derived stem cells (ASCs) and the adrenocortical cancer cell line H295R leads to metabolic and functional reprogramming of both cell types: cancer cells limit differentiation and increase proliferation of ASCs, which in turn support tumor growth and invasion. This effect associates with a shift from the paracrine cancer-promoting IGF2 axis towards an ASC-associated leptin axis, along with a shift in the SDF-1 axis towards CXCR7 expression in H295R cells. In conclusion, our findings suggest that adipose precursors, as pivotal components of the ACC microenvironment, promote cancer cell reprogramming and invasion, opening new perspectives for the development of more effective therapeutic approaches.

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Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

International Journal of Molecular Sciences ◽

10.3390/ijms21218153 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8153

Author(s):

Kimin Kim ◽

Yeh Joo Sohn ◽

Ruri Lee ◽

Hye Ju Yoo ◽

Ji Yoon Kang ◽

...

Keyword(s):

Endothelial Cells ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Cell Types ◽

Cancer Drug ◽

Cancer Microenvironment ◽

Cancer Associated Fibroblasts ◽

Cancer Cell Invasion

Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.

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Anticancer Effect of Fucoidan in Combination with Tyrosine Kinase Inhibitor Lapatinib

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/865375 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Byeongsang Oh ◽

Jihun Kim ◽

Weidong Lu ◽

David Rosenthal

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Kinase Inhibitor ◽

Cell Types ◽

Anticancer Effect ◽

Inhibit Cell Growth ◽

Mechanism Of Interaction ◽

Synergistic Antitumor Activity

Background. Despite a number ofin vitroandin vivostudies reporting the efficacy of fucoidan in treating various cancers, few studies have measured the efficacy of dietary fucoidan (DF) in combination with cancer drugs. Thus, we examined the sensitivity of DF in combination with the EGFR/ERBB2-targeting reagent lapatinib on cancer cells.Method. We selected six EGFR/ERBB2-amplified cancer cell lines (OE19, NCI-N87, OE33, ESO26, MKN7, and BT474) as anin vitromodel and tested their sensitivity to DF alone and to DF in combination with the well-known EGFR/ERBB2-targeting reagent lapatinib.Result. Overall, in drug independent sensitivity test, DF alone did not significantly inhibit the growth of EGFR/ERBB2-amplified cancer cellsin vitro. When DF was given in combination with lapatinib, however, it tended to synergistically inhibit cell growth in OE33 but antagonized the action of lapatinib in ESO26, NCI-N87, and OE19.Conclusion. This study suggests that DF has the potential to increase or decrease the effects of certain anticancer drugs on certain cancer cell types. Further study is needed to explore the mechanism of interaction and synergistic antitumor activity of DF in combination with chemotherapy and targeted therapy.

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Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720693115 ◽

2018 ◽

Vol 115 (8) ◽

pp. 1789-1794 ◽

Cited By ~ 19

Author(s):

Felipe Paredes ◽

Kely Sheldon ◽

Bernard Lassègue ◽

Holly C. Williams ◽

Elizabeth A. Faidley ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Substrate Inhibition ◽

Mitochondrial Protein ◽

Hypoxia Inducible Factor ◽

Cell Types ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Prosthetic Group ◽

Catabolic Enzymes

Although the addition of the prosthetic group lipoate is essential to the activity of critical mitochondrial catabolic enzymes, its regulation is unknown. Here, we show that lipoylation of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (αKDH) complexes is a dynamically regulated process that is inhibited under hypoxia and in cancer cells to restrain mitochondrial respiration. Mechanistically, we found that the polymerase-δ interacting protein 2 (Poldip2), a nuclear-encoded mitochondrial protein of unknown function, controls the lipoylation of the pyruvate and α-KDH dihydrolipoamide acetyltransferase subunits by a mechanism that involves regulation of the caseinolytic peptidase (Clp)-protease complex and degradation of the lipoate-activating enzyme Ac-CoA synthetase medium-chain family member 1 (ACSM1). ACSM1 is required for the utilization of lipoic acid derived from a salvage pathway, an unacknowledged lipoylation mechanism. In Poldip2-deficient cells, reduced lipoylation represses mitochondrial function and induces the stabilization of hypoxia-inducible factor 1α (HIF-1α) by loss of substrate inhibition of prolyl-4-hydroxylases (PHDs). HIF-1α–mediated retrograde signaling results in a metabolic reprogramming that resembles hypoxic and cancer cell adaptation. Indeed, we observe that Poldip2 expression is down-regulated by hypoxia in a variety of cell types and basally repressed in triple-negative cancer cells, leading to inhibition of lipoylation of the pyruvate and α-KDH complexes and mitochondrial dysfunction. Increasing mitochondrial lipoylation by forced expression of Poldip2 increases respiration and reduces the growth rate of cancer cells. Our work unveils a regulatory mechanism of catabolic enzymes required for metabolic plasticity and highlights the role of Poldip2 as key during hypoxia and cancer cell metabolic adaptation.

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