The aegis: platelets as biomarkers of tumor progression

2020 ◽  
Vol 14 (7) ◽  
pp. 573-585
Author(s):  
Tanya N Augustine
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Tumor Cells ◽  
High Velocity ◽  
Reciprocal Cross ◽  
Bioactive Molecules ◽  
Metastatic Niche ◽  
Metastatic Process ◽  
Growth Promoting

There is increasing awareness that platelets play a significant role in creating a hypercoagulable environment that mediates tumor progression, beyond their classical hemostatic function. Platelets have heterogenic responses to agonists, and differential release and uptake of bioactive molecules may be manipulated via reciprocal cross-talk with cells of the tumor microenvironment. Platelets thus promote tumor progression by enhancing tumor growth, promoting the development of tumor-associated vasculature and encouraging invasion. In the metastatic process, platelets form the shield that protects tumor cells from high-velocity forces and immunosurveillance, while ensuring the establishment of the pre-metastatic niche. This review presents the complexity of these concepts, considering platelets as biomarkers for diagnosis, prognosis and potentially as therapeutic targets in cancer.

scholarly journals Cancer: An Oxidative Crosstalk between Solid Tumor Cells and Cancer Associated Fibroblasts

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Alessandro Arcucci ◽  
Maria Rosaria Ruocco ◽  
Giuseppina Granato ◽  
Anna Maria Sacco ◽  
Stefania Montagnani
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Antioxidant Systems ◽  
Activation Process ◽  
Cancer Associated Fibroblasts

Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

scholarly journals Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000489 ◽  
Author(s):  
Marta Di Martile ◽  
Valentina Farini ◽  
Francesca Maria Consonni ◽  
Daniela Trisciuoglio ◽  
Marianna Desideri ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Macrophage Polarization ◽  
Melanoma Cells ◽  
Response To Therapy ◽  
Major Constituent ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.

scholarly journals The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

2020 ◽  
Vol 11 ◽  
Author(s):  
Shahid Hussain ◽  
Bo Peng ◽  
Mathew Cherian ◽  
Jonathan W. Song ◽  
Dinesh K. Ahirwar ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Tumor Development ◽  
Inflammatory Cells ◽  
Host Cells ◽  
Metastatic Niche ◽  
Cancer Pathogenesis ◽  
Cancer Metastases ◽  
Cellular Components

The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a “pre-metastatic niche” like a “soil” in distant organs whereby circulating tumor cells “seed’ and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.

scholarly journals WNT vampirization by glioblastoma leads to tumor growth and neurodegeneration

2018 ◽  
Author(s):  
Marta Portela ◽  
Varun Venkataramani ◽  
Natasha Fahey-Lozano ◽  
Esther Seco ◽  
Maria Losada-Perez ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Growth ◽  
Wnt Signaling ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Wnt Pathway ◽  
Integration Site ◽  
Infiltration Capacity ◽  
Xenograft Models

SummaryGlioblastoma (GB) is the most lethal brain tumor due to its high proliferation, aggressiveness, infiltration capacity and resilience to current treatments. Activation of the Wingless-related-integration-site (WNT) pathway is associated with a bad prognosis. Using Drosophila and primary xenograft models of human GB, we describe a mechanism that leads to the activation of WNT signaling [Wingless (Wg) in Drosophila] in tumor cells. GB cells display a network of tumor microtubes (TMs) which enwraps neurons, accumulates Wg receptor Frizzled1 (Fz1), and, thereby, actively depletes Wg from the neurons. Consequently, GB cells proliferate due to β-catenin activation, and neurons degenerate due to Wg signaling extinction. This novel view explains both neuron-dependent tumor progression, and also the neural decay associated with GB.

scholarly journals CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

2021 ◽  
Vol 11 ◽  
Author(s):  
Gurcan Gunaydin
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Poor Prognosis ◽  
Cancer Associated Fibroblasts ◽  
Mutual Relationship ◽  
Complex Interplay ◽  
Tumor Immune Evasion ◽  
Mechanisms Of Carcinogenesis

Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

High-diluted thymulin on Ehrlich tumor growth in mice and the importance of tumor microenvironment

2021 ◽  
Vol 17 (3-4) ◽  
pp. 20-41
Author(s):  
Juliana Gimenez Amaral ◽  
Thayna Neves Cardoso ◽  
Aloísio Cunha De Carvalho ◽  
Cideli de Paula Coelho ◽  
Silvia Waisse ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Spleen Cell ◽  
Tumor Cells ◽  
Caspase 3 ◽  
Tumor Growth Rate ◽  
Cell Populations ◽  
Ehrlich Tumor ◽  
Systemic Immune Response

Introduction: The aim of the present study was to describe different biological aspects of Ehrlich tumor in mice, such as body weight evolution, tumor growth rate, histological organization and systemic immune response after treatment with high-diluted thymulin (10-9 M, named 5CH). Methods: Tumor assessment was focused on macro- and microscopic aspects; parameters included occurrence of necrosis, embolism and tumor development, in addition to quantitative analysis of apoptosis (caspase-3), cell proliferation (Ki-67) and angiogenesis (vascular endothelial growth factor - VEGF) by means of specific immunohistochemistry markers. Spleen cell populations were evaluated by flow cytometry analysis. Results: Mice treated with thymulin 5CH exhibited changes in the tumor microenvironment, such as reduced micro-embolism incidence and cytokeratin expression, with increased caspase-3 expression in the tumor cells. These findings indicate some apoptotic activity by the tumor cells induced by the treatment, even though no reduction of the macroscopic tumor mass occurred. No changes in the systemic immune response were detected, as the balance among spleen cell populations remained unchanged. Conclusions: The results indicate that treatment of mice bearing Ehrlich tumor with thymulin 5CH induces some specific changes in the tumor environment. However, it did not influence systemic immunity parameters. Adjuvant use of thymulin 5CH in oncological clinical practice is still a matter of discussion.

μ Opioid Receptor Stimulates a Growth Promoting and Pro-Angiogenic Tumor Microenvironment by Transactivating VEGF Receptor-2/Flk-1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3687-3687
Author(s):  
Elliot J. Stephenson ◽  
Humberto J. Martinez-Suarez ◽  
Mariya Farooqui ◽  
Debabrata Mukhopadhyay ◽  
Deborah A. Hughes ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Opioid Receptor ◽  
Calcium Release ◽  
Small Gtpase ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Growth Promoting ◽  
Stimulation Of

Abstract Like VEGF, morphine stimulates MAPK/ERK and Akt, leading to the promotion of angiogenesis via NO dependent signaling (Cancer Res62: 4491, 2002). Morphine acts via pertussis toxin (PT)-dependent G-protein coupled receptors (GPCRS), while VEGF acts via receptor tyrosine kinases (RTKs). We showed that PT-dependent GPCRs transactivate VEGF receptor-2/Flk1 via small GTPase RhoA (JBC277: 4679, 2002; JBC278:20738, 2003). Therefore, we hypothesized that morphine via the mu opioid receptor (MOR) transactivates Flk1 and promotes a pro-angiogenic microenvironment. Morphine-induced proliferation of human umbilical vein endothelial cells (HUVEC) was completely abrogated by Y-27632 (100 μM), a highly selective and potent inhibitor of Rho-associated protein kinases, suggesting the activation of Rho signaling by morphine. Addition of 1 μM morphine potentiated VEGF-induced (10 ng/ml) proliferation of HUVEC by 25%. We observed a 30% increase in intracellular calcium release after VEGF stimulation of HUVEC pre-incubated with morphine as compared to HUVEC pre-incubated with PBS, detected by a change in the fluorescence ratio of the Fura-2 AM dye. These findings show that morphine, via MOR and Rho signaling, transactivates Flk1 leading to the stimulation of calcium signaling and endothelial cell proliferation. To functionally corroborate our hypothesis, we used MOR knockout (MOR-KO) mice and injected them with MOR-replete T241 fibrosarcoma cells. T241 fibrosarcoma tumor growth in vivo showed appearance of palpable and measurable tumors 2 days earlier in wild type (wt) as compared to MOR-KO mice. Tumor growth and angiogenesis were decreased by 20–35% in MOR-KO mice as compared to wt littermates during 3 weeks of tumor growth. None of the MOR-KO showed signs of lung metastasis versus 40% wt mice with metastasis. Morphine (1.42 for the first 2 wks and 2.14 mg/Kg/day later, respectively) stimulated 20–35% tumor growth in wt, but not in MOR-KO mice. Western immunoblotting showed a 10-fold increase in the expression of phospho-Flk1 in morphine treated wt tumors as compared to PBS-treated wt mice. Morphine did not stimulate phospho-Flk1 expression in MOR-KO mice. Western analysis of immunoprecipitates obtained with α-MOR antibody showed the expression of Flk1 and phospho-Flk1 in wt, but were not expressed in MOR-KO tumors. Thus, MOR stimulates the transactivation of Flk1 in wt mice but not in MOR-KO. These in vitro and in vivo data using MOR-KO mice and the MOR agonist, morphine, show that MOR stimulates endothelial proliferation, angiogenesis and promotes tumor growth and metastasis directly as well as by transactivating Flk1 phosphorylation. We speculate that MOR is a critical component of the ‘angiogenic switch’, which regulates the pro-angiogenic and growth promoting tumor microenvironment. Thus, MOR provides a novel target for developing anti-angiogenic therapies.

Platelet Depletion Reduces Tumor Hypoxia and Metastasis Mediated by Met Signaling Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3321-3321
Author(s):  
Rong Li ◽  
Meiping Ren ◽  
Ni Chen ◽  
Mao Luo ◽  
Jianbo Wu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Hypoxia ◽  
Hemoglobin Content ◽  
Melanoma Cancer ◽  
And Control ◽  
Platelet Depletion

Abstract Abstract 3321 Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hemorrhagic metastasis. However, the role of platelets in the tumor growth, angiogenesis, and metastasis initiation remains undefined. The B16/F10 melanoma cancer cells model of metastasis and the Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model were used for this purpose. Using induction of thrombocytopenia, primary tumor growth was monitored and every 3 days anti-GPIbα or rat IgG injections were initiated when tumor reached ∼500mm3and continued until tumor reached to 3 weeks. We showed that platelet depletion had no change in tumor growth but reduced metastasis. Platelet depletion significantly increased pericyte coverage and reduced vascular density compared with control mice. We evaluated the ratio of fluorescence intensities within the plasma and tumor following injection of mice with FITC-dextran. We found that the FITC-dextran was similarly deposited into the tumor tissue in either platelet-depleted or control mice, indicating that tumor vessel perfusion did not differ in either platelet-depleted or control mice. To further gain insight into the molecular mechanisms associated with reduced metastasis resulting from platelet depletion, we assessed hypoxia levels by examining pimonidazole adduct formation in the tumors of platelet-depleted and control mice and found decreased hypoxic levels in the platelet-depleted tumors. In addition, expression of the hypoxia-inducible transcription factor HIF-1α was also significantly reduced in the tumors of platelet-depleted mice. Tumor hypoxia is strongly associated with deposition of hemoglobin. We measured the intratumor hemoglobin content, reflecting the level of erythrocytes extravasation. The hemoglobin content in the tumors of mice with platelet-depletion was significantly higher than that of control mice (172.11 ± 20.2 g/L/g Vs. 110.28 ± 12.4 g/L/g, p<0.05) Based on the known induction effects of hypoxia and cancer invasiveness on the expression and activation of the proinvasive tyrosine kinase receptor Met, we analyzed total protein and tyrosine phosphorylation levels of Met in both platelet-depleted and control mice. Western blotting analysis revealed that platelet-depletion caused a significantly decrease of both total Met and phosph-Met in tumors when compared to tumors from control mice. To evaluate intratumoral growth factor level, microdialysis was performed after 3 weeks and there was a significant decrease of extracellular VEGF and TNF-β in platelet depletion mice compared with control mice. Recent studies demonstrated that abundant platelets were detected in the tumor microenvironment apart from the vasculature. Based on the finding platelets in contact with tumor cells outside the bloodstream, we examined the functional effects of co-implantation of B16/F10 tumor cells with platelets on tumor progression and metastasis. B16/F10 melanoma cancer cells were implanted into back of wild type mice. During a 3-weeks growth, co-implantation of B16/F10 with platelets not only led to promoted tumor volume (3968 ± 296 mm3Vs. 2956 ± 180 mm3, p<0.05) and weight (5.529 ± 0.35 g Vs. 3.943 ± 0.738 g, p<0.05 ) compared with B16/F10 alone implantation, but also led to an increase in metastasis. Furthermore, in vitro co-culture of B16/F10 cancer cells with platelets showed a significant increase in B16/F10 cancer cells invasion compared with B16/F10 cancer cells alone. In conclusion, our findings demonstrate for the first time that platelets play a critical role in the initiation of tumor metastasis. Moreover, our findings suggest that platelets within the primary tumor microenvironment are likely involved in tumor progression and metastasis. Disclosures: No relevant conflicts of interest to declare.

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