scholarly journals Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2486
Author(s):  
Ronit Vogt Sionov
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cell ◽  
Neutrophil Function ◽  
The Body ◽  
Cathepsin G ◽  
Metastatic Sites

Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

Protease Activated Receptor-1 (PAR-1) Impedes Tumor Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2560-2560
Author(s):  
Gregory N. Adams ◽  
Haley Weston ◽  
Leah Rosenfeldt ◽  
Malinda Frederick ◽  
Joseph S. Palumbo
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Prostate Tumor ◽  
Protease Activated Receptor 1 ◽  
Tumor Types ◽  
And Control

Abstract Activation of cell signaling by thrombin through Protease Activated Receptor-1 (PAR-1) represents one important interface between blood coagulation and cell activation in response to injury and inflammation. In the context of cancer, PAR-1 has been suggested to promote tumor growth through mechanisms coupled to tumor cell proliferation, tumor cell migration, and the development of a supportive tumor stroma. Consistent with this view, both tumor cells and stromal cells express high levels of PAR-1, and elevated PAR-1 expression has been correlated with a poor prognosis across several tumor types. In the current studies, we tested the hypothesis that PAR-1 is a critical driver of tumorigenesis and tumor growth using murine models of genetically-induced prostate and intestinal tumor growth. To define the role of PAR-1 in prostate tumor progression, we interbred mice expressing the TRAMP transgene (transgenic adenocarcinoma of the mouse prostate; SV40 Large T antigen under the control of a probasin promoter) to PAR-1-deficient mice (PAR-1-/-) in order to generate male TRAMP mice with and without PAR-1 expression for detailed analyses of prostate tumor growth. Surprisingly, prostate tumors harvested from PAR-1-/- mice were significantly larger than those harvested from PAR-1+/+ mice. In order to begin to address the PAR-1 expressing cellular compartments responsible for prostate tumor inhibition, we subcutaneously inoculated immunocompetent C57Bl/6-derived PAR-1-/- and control mice with tumor cells derived from a C57Bl/6 TRAMP mouse. TRAMP-derived tumors grew indistinguishably in PAR-1-/- and control mice, suggesting that stromal-cell associated PAR-1 is dispensable for prostate tumor growth. We next tested the effect of tumor cell-intrinsic inhibition of PAR-1 in TRAMP tumor cells by viral transduction with a construct containing an shRNA against murine PAR-1 in parallel to a non-specific shRNA construct. Diminishing tumor cell-associated PAR-1 expression resulted in significantly more rapid tumor growth in vivo. In order to better define the role of tumor cell-intrinsic PAR-1 we harvested TRAMP tumor cells from a PAR-1 deficient mouse and grew these cells in vitro. We transduced these PAR-1-deficient prostate tumor cells with viral vectors conferring expression of WT murine PAR-1 (PAR-1+), a PAR-1 mutant lacking the thrombin cleavage (R41A mutant) or empty vector (PAR-1-). PAR-1- cells grew robustly and similarly to the parental cells in vitro with a doubling time of approximately 48 hours. Cells expressing the R41A mutant PAR-1 also grew robustly and similarly to PAR-1 deficient cells. However, PAR-1+ cells failed to show any signs of cell proliferation over the span of a 4 day observation period. Furthermore, PAR-1 expression dramatically altered the ability of TRAMP cells to demonstrate signs of cell spreading as measured by the frequency of pseudopodia per cell. As a means of determining the role of PAR-1 in tumorigenesis and tumor growth in another spontaneously occurring setting, we interbred PAR-1-/- mice with APCMin/+ mice genetically predisposed to intestinal adenoma formation due to loss of heterozygosity of the tumor suppressor adenomatous polyposis coli gene. Blinded quantitative histological analyses of the intestinal tracts of PAR-1-/- and PAR-1+/+ APCMin/+ mice revealed that PAR-1 deficiency resulted in a significant 2-fold increase in the number of adenomas observed. Furthermore, the adenomas observed in PAR-1-/- mice were significantly larger based on morphometric analyses of adenoma surface area in histological sections. In sum, these data demonstrate a surprising and unexpected role for PAR-1 in the inhibition of tumor growth in the context of two distinct tumor types. Disclosures No relevant conflicts of interest to declare.

scholarly journals MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination

2021 ◽  
Vol 9 (3) ◽  
pp. e001388
Author(s):  
Xiaofang Wu ◽  
Marie Nelson ◽  
Mousumi Basu ◽  
Priya Srinivasan ◽  
Christopher Lazarski ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Tumor Escape ◽  
Human Neuroblastoma ◽  
Whole Cell ◽  
Myc Oncogene ◽  
Immune Cell Infiltrates

BackgroundMYC oncogene is deregulated in 70% of all human cancers and is associated with multiple oncogenic functions including immunosuppression in the tumor microenvironment. The role of MYC in the immune microenvironment of neuroblastoma and melanoma is investigated and the effect of targeting Myc on immunogenicity of cancer cells is evaluated.MethodsImmune cell infiltrates and immunogenic pathway signatures in the context of MYCN amplification were analyzed in human neuroblastoma tumors and in metastatic melanoma. Dose response and cell susceptibility to MYC inhibitors (I-BET726 and JQ1) were determined in mouse cell lines. The influence of downregulating Myc in tumor cells was characterized by immunogenic pathway signatures and functional assays. Myc-suppressed tumor cells were used as whole cell vaccines in preclinical neuroblastoma and melanoma models.ResultsAnalysis of immune phenotype in human neuroblastoma and melanoma tumors revealed that MYCN or c-MYC amplified tumors respectively are associated with suppressed immune cell infiltrates and functional pathways. Targeting Myc in cancer cells with I-BET726 and JQ1 results in cell cycle arrest and induces cell immunogenicity. Combining vaccination of Myc-inhibited tumor cells with checkpoint inhibition induced robust antitumor immunity and resulted in therapeutic cancer vaccine therapy in mouse neuroblastoma tumors. Despite vigorous antitumor immunity in the mouse melanoma model, upregulation of immunosuppressive pathways enabled tumor escape.ConclusionsThis study demonstrates that the Myc oncogene is an appropriate target for inducing tumor cell immunogenicity and suggests that Myc-suppressed whole tumor cells combined with checkpoint therapy could be used for formulating a personalized therapeutic tumor vaccine.

An Early Robot Architecture for Cancer Healing

2011 ◽  
Vol 2 (4) ◽  
pp. 57-71
Author(s):  
Mohamed Abdelhamid Abbas
Keyword(s):  
Cancer Research ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Temperature Sensor ◽  
Chemical Sensor ◽  
Pine Needle ◽  
Robot Architecture ◽  
Cancer Tumor

Treating cancer tumors is a main goal of cancer research. The author of this paper identify a new manner to treat cancer tumors more effectively using a recommended architecture of a nanorobot called CANBOT. It contains a number of nano-components: an actuator, temperature sensor, chemical sensor, and microcontroller. CANBOT starts its role by moving toward the tumor cells using the actuator. It senses the tumor cell by capturing its image and sensing its chemicals by the chemical sensor. When CANBOT distinguishes the tumor, it verifies the survival of the tumor cells by its temperature sensor. CANBOT increases the temperature of the tumor cell through the warmer. Sensing of the cancer chemicals starts over to detect the remaining existence of cancer cells. The suggested nanorobot injects the cell with the drug from a tiny tank throughout a nano pump with a small pine needle. A nano-microcontroller controls the mechanism of CANBOT formative the role of each one and the appropriate sequences. The position of the proposed nanorobot is simulated with reference to the position of the tumor using an analytical model. The conclusion is drawn that destroying the tumor requires instilling the robot into the cancer tumor directly for effective treatment.

scholarly journals PD-L1 promotes tumor growth and progression by activating WIP and β-catenin signaling pathways and predicts poor prognosis in lung cancer

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Wendan Yu ◽  
Yijun Hua ◽  
Huijuan Qiu ◽  
Jiaojiao Hao ◽  
Kun Zou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Migration And Invasion

Abstract PD-L1 is overexpressed in tumor cells and contributes to cancer immunoevasion. However, the role of the tumor cell-intrinsic PD-L1 in cancers remains unknown. Here we show that PD-L1 regulates lung cancer growth and progression by targeting the WIP and β-catenin signaling. Overexpression of PD-L1 promotes tumor cell growth, migration and invasion in lung cancer cells, whereas PD-L1 knockdown has the opposite effects. We have also identified WIP as a new downstream target of PD-L1 in lung cancer. PD-L1 positively modulates the expression of WIP. Knockdown of WIP also inhibits cell viability and colony formation, whereas PD-L1 overexpression can reverse this inhibition effects. In addition, PD-L1 can upregulate β-catenin by inhibiting its degradation through PI3K/Akt signaling pathway. Moreover, we show that in lung cancer cells β-catenin can bind to the WIP promoter and activate its transcription, which can be promoted by PD-L1 overexpression. The in vivo experiments in a human lung cancer mouse model have also confirmed the PD-L1-mediated promotion of tumor growth and progression through activating the WIP and β-catenin pathways. Furthermore, we demonstrate that PD-L1 expression is positively correlated with WIP in tumor tissues of human adenocarcinoma patients and the high expression of PD-L1 and WIP predicts poor prognosis. Collectively, our results provide new insights into understanding the pro-tumorigenic role of PD-L1 and its regulatory mechanism on WIP in lung cancer, and suggest that the PD-L1/Akt/β-catenin/WIP signaling axis may be a potential therapeutic target for lung cancers.

scholarly journals 890 Manipulation of epithelial-to-mesenchymal transition reveals metastatic breast cancers support immune suppression via heme metabolism

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A933-A933
Author(s):  
Michelle Williams ◽  
Sabrina Hafeez ◽  
Jessica Christenson ◽  
Nicole Spoelstra ◽  
Jill Slansky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Conditioned Medium ◽  
Tumor Cells ◽  
Immune Suppression ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Mesenchymal Transition ◽  
Heme Metabolism

BackgroundOncogenic epithelial-to-mesenchymal transition (EMT) enhances triple negative breast cancer (TNBC) aggressiveness and immune suppression. To identify alternative immunotherapy targets for metastatic TNBC, we reversed EMT in mesenchymal-like human TNBC and mouse mammary carcinoma models by restoring the micro-RNA-200c. This approach identified several tumor cell metabolizing enzymes with potential immune modulatory functions such as heme oxygenase-1 (HO-1). HO-1 converts heme to bilirubin, an established immune suppressor in other diseases that has never been tested as such in cancer. We hypothesize that tumor cell-HO-1 activity and subsequent bilirubin secretion enhance TNBC metastasis by supporting a pro-tumor immune microenvironment (figure 1).MethodsWe tested the impact of tumor cell-HO-1 and bilirubin on macrophage immune suppression and efferocytic capacity (engulfment of dead tumor cells) using qRT-PCR, flow cytometry and live cell imaging. Human and mouse macrophages were analyzed after treatment with exogenous bilirubin or bilirubin-depleted conditioned medium collected from tumor cells treated with tin mesoporphyrin (SnMP), an enzymatic HO-1 inhibitor. Primary tumor growth and lung metastatic burden were observed in syngeneic mice harboring HO-1 depleted 66Cl-4 mammary tumors (shRNA). Breast cancer specimens were analyzed via CIBERSORT to predict immune cell abundance in patients with high versus low levels of heme metabolism genes.ResultsMacrophages cultured with conditioned medium from tumor cells treated with the HO-1 inhibitor SnMP demonstrated a 35–65% decrease in immune suppressive genes (Arg1, Cd274, Tgfb1) compared to those treated with control conditioned medium. This effect was rescued by exogenous treatment with 2.5 µM bilirubin. Direct bilirubin treatment enhanced macrophage PD-L1 mRNA and protein expression by at least 6-fold. In contrast, bilirubin decreased expression of macrophage efferocytosis genes (Mertk, Tyro3) by at least 50%, resulting in decreased efferocytic capacity. To test whether bilirubin supports tumor progression via modulation of macrophages, we evaluated tumor growth and metastasis after tumor cell-HO-1 depletion. While mice with shHO1 tumors had enhanced primary tumor growth compared to those with shCnt tumors, HO-1 depletion decreased lung metastatic capacity. Although immune cell infiltration and activation is currently underway in this mouse model, CIBERSORT analysis revealed that breast cancer specimens with high levels of heme metabolism genes have a predicted increase in M2 macrophage presence.Abstract 890 Figure 1Project modelHeme oxygease-1 (HO-1) breaks down heme into immune modulatory products such as bilirubin (BR). We demonstrated that tumor cell-secreted BR may enhance TNBC lung metastasis by supporting macrophage immune suppression and dysfunction. This can be blocked by genetic (shRNA) or pharmacologic (SnMP) inhibition of HO-1 in TNBC cells. Figure made with biorender.com.ConclusionsTumor cell-HO-1 may support immune cell suppression and dysfunction during breast cancer metastasis via bilirubin. Since HO-1 inhibitors including SnMP are FDA approved for treatment of other diseases, these findings could rapidly be translated to provide an additional immunotherapy for metastatic TNBC.

scholarly journals Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

2021 ◽  
Vol 22 (17) ◽  
pp. 9121
Author(s):  
De Pradip ◽  
Aske Jennifer ◽  
Dey Nandini
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cross Talk ◽  
Critical Role ◽  
Immune Surveillance ◽  
Endometrial Cancers

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

Role of Erythropoietin as an Angiogenic Factor and Target in Cancer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 416-416
Author(s):  
Murat O. Arcasoy ◽  
Matthew E. Hardee ◽  
Xiaohong Jiang ◽  
Mark W. Dewhirst
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Angiogenesis ◽  
Angiogenic Factor ◽  
Fat Pad ◽  
Significant Stimulation ◽  
Mammary Fat Pad ◽  
Angiogenic Effect

Abstract Erythropoietin is a pleiotropic cytokine with diverse non-hematopoietic functions. Epo and its receptor EpoR have been implicated in the physiologic angiogenesis that occurs in the mouse embryo, female genital tract and during wound healing. Epo is involved in the pathologic angiogenesis of diabetic retinopathy but the role of Epo in tumor angiogenesis, a pathologic process that is essential for tumor progression, is not established. We investigated the hypothesis that Epo may play an important role in tumor cell-induced angiogenesis and progression. Fluorescently-labeled rodent mammary carcinoma cells were implanted in dorsal skin-fold window chambers in nu/nu mice, a model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously during the initial stages of tumor formation. Tumor angiogenesis (vascular length density, VLD) and growth (tumor area) were measured serially over 8 days using intravital microscopy and computerized image analysis. Co-injection of Epo with implanted tumor cells significantly increased VLD by 78% compared to vehicle-injected controls (p<0.001 by repeated measures ANOVA and Bonferroni test, n=8 mice/group). This early proangiogenic effect was associated with significant stimulation of tumor growth by 66% (p<0.001). Implantation of R3230-GFP cells engineered to stably express a constitutively active EpoR mutant (R129C) resulted in significant stimulation of neovascularization by 76% (p<0.001, n=7) and increased tumor growth by 79% compared to empty vector-transfected control cells (p<0.001). To target endogenous Epo function in window chambers, recombinant soluble EpoR (sEpoR) or a neutralizing anti-Epo monoclonal antibody (mAb) were co-injected at the time of tumor cell implantation. By day 8, marked inhibition of neovascularization was observed in response to treatment with sEpoR (44% reduction) or mAb (47% reduction) compared to vehicle-injected controls (p<0.001, n=7). This anti-angiogenic effect was associated with significant decrease in tumor size by 37% (sEpoR) and 39% (mAb), respectively (p<0.001). Stable expression of a secreted Epo antagonist (Epo-R103A) protein in tumor cells was associated with a remarkable anti-angiogenic effect with 50% reduction in VLD (p<0.001, n=7) and near complete disappearance of tumor cells by day 8 compared to controls (p<0.001). Analysis of two independent single cell clones of each transfected cell line showed similar results. All transfected cell lines exhibited similar in vitro growth characteristics and cell cycle profile. To further assess in vivo tumor growth, cells were implanted orthotopically in the mammary fat pad of female nu/nu mice (10 animals/group). EpoR-R129C expression was associated with significantly increased tumor volume (531±41 mm3, n=10) compared to vector-transfected cells (232±46 mm3, n=7). EpoR-R129C tumors exhibited significantly increased numbers of positive cells for proliferation marker Ki67 and blood vessel marker CD31 per high power field (p=0.0006 and 0.0008, respectively). Remarkably, tumor growth was completely absent after mammary fat pad implantation of R3230-GFP cells secreting the antagonist R103A-Epo protein (n=10 mice) compared to controls (183±46 mm3, n=8). Taken together, these data indicate that 1)-Epo is an important angiogenic factor that modulates tumor cell-induced angiogenesis and 2)-Suppression of tumor angiogenesis and progression by Epo blockade suggests that Epo may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

An Early Robot Architecture for Cancer Healing

2012 ◽  
pp. 272-286
Author(s):  
Mohamed Abdelhamid Abbas
Keyword(s):  
Cancer Research ◽  
Tumor Cell ◽  
Effective Treatment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Temperature Sensor ◽  
Chemical Sensor ◽  
Robot Architecture ◽  
Cancer Tumor

Treating cancer tumors is a main goal of cancer research. The author of this paper identifies a new manner to treat cancer tumors more effectively using a recommended architecture of a nanorobot called CANBOT. It contains a number of nano-components: an actuator, temperature sensor, chemical sensor, and microcontroller. CANBOT starts its role by moving toward the tumor cells using the actuator. It senses the tumor cell by capturing its image and sensing its chemicals by the chemical sensor. When CANBOT distinguishes the tumor, it verifies the survival of the tumor cells by its temperature sensor. CANBOT increases the temperature of the tumor cell through the warmer. Sensing of the cancer chemicals starts over to detect the remaining existence of cancer cells. The suggested nanorobot injects the cell with the drug from a tiny tank throughout a nano pump with a small pine needle. A nano-microcontroller controls the mechanism of CANBOT formative the role of each one and the appropriate sequences. The position of the proposed nanorobot is simulated with reference to the position of the tumor using an analytical model. The conclusion is drawn that destroying the tumor requires instilling the robot into the cancer tumor directly for effective treatment.

scholarly journals CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM)

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2459
Author(s):  
Anja Kathrin Wege ◽  
Tobias F. Dreyer ◽  
Attila Teoman ◽  
Olaf Ortmann ◽  
Gero Brockhoff ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Immune Cell ◽  
Lung Metastases ◽  
Tumor Cell Proliferation ◽  
Trastuzumab Treatment ◽  
The Impact

CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells. Moreover, we evaluated the therapeutic capacity of Matrix-Metalloproteinases-inhibitors TMI-1 and GI254023X in combination with the anti-HER2 antibody trastuzumab in vitro and in vivo. TMI-1 and GI254023X caused a reduced shedding of CX3CL1 and of HER2 in vitro but without effects on tumor cell proliferation or viability. In addition, trastuzumab treatment did not retard MDA-MB-453 cell expansion in vitro unless CX3CL1 was overexpressed upon transfection (MDA-MB-453CX3CL1). In humanized tumor mice, which show a coexistence of human tumor and human immune system, CX3CL1 overexpression resulted in a slightly enhanced tumor growth. However, trastuzumab treatment attenuated tumor growth of both MDA-MB-453CX3CL1 and empty vector transfected MDA-MB-453 transplanted mice but showed enhanced efficiency especially in preventing lung metastases in CX3CL1 overexpressing cancer cells. However, TMI-1 did not further enhance the trastuzumab treatment efficacy.

scholarly journals Depleting RhoA/Stress Fiber-Organized Fibronectin Matrices on Tumor Cells Non-Autonomously Aggravates Fibroblast-Driven Tumor Cell Growth

2020 ◽  
Vol 21 (21) ◽  
pp. 8272
Author(s):  
Li-Tzu Huang ◽  
Chen-Lung Tsai ◽  
Shin-Huei Huang ◽  
Ming-Min Chang ◽  
Wen-Tsan Chang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Stress Fiber ◽  
Tumor Cell Growth ◽  
Primary Tumor Growth

Fibronectin (FN) expressed by tumor cells has been known to be tumor suppressive but the pericellular FN (periFN) assembled on circulating tumor cells appears to evidently promote distant metastasis. Whereas the regulation of periFN assembly in suspended cells has currently been under investigation, how it is regulated in adherent tumor cells and the role of periFN in primary tumor growth remain elusive. Techniques of RNAi, plasmid transfections, immunoblotting, fluorescence/immunohistochemistry staining, cell proliferation assays, and primary tumor growth in C57BL6 mice and Fischer 344 rats were employed in this study. We found that endogenously synthesized FN in adherent tumor cells was required for periFN assembly which was aligned by RhoA-organized actin stress fiber (SF). Depleting periFN on adherent tumor cells congruently promoted in vivo tumor growth but surprisingly did not autonomously impact on in vitro tumor cell proliferation and apoptosis, suggestive of a non-autonomous role of periFN in in vivo tumor growth. We showed that the proliferative ability of shFN-expressing tumor cells was higher than shScramble cells did in the presence of fibroblasts. Altogether, these results suggested that depriving RhoA/SF-regulated periFN matrices non-autonomously promotes fibroblast-mediated tumor cell growth.

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