POTENT ANTITUMOR EFFECTS OF CD154 TRANSDUCED TUMOR CELLS IN EXPERIMENTAL BLADDER CANCER

Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.

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901 Non-muscle invasive bladder cancer and circulating tumor cells: Individuation and prognostic value

European Urology Supplements ◽

10.1016/s1569-9056(12)60898-7 ◽

2012 ◽

Vol 11 (1) ◽

pp. e901-e901a

Author(s):

G.M. Busetto ◽

R. Giovannone ◽

G. Antonini ◽

M. Di Placido ◽

A. Petracca ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Prognostic Value ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

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RGD4C peptide mediates anti-p21Ras scFv entry into tumor cells and produces an inhibitory effect on the human colon cancer cell line SW480

BMC Cancer ◽

10.1186/s12885-021-08056-4 ◽

2021 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Chen-Chen Huang ◽

Fang-Rui Liu ◽

Qiang Feng ◽

Xin-Yan Pan ◽

Shu-Ling Song ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Membrane ◽

Fusion Protein ◽

Tumor Cell ◽

Tumor Cells ◽

Fusion Proteins ◽

Inhibitory Effect ◽

Endosomal Escape ◽

Antitumor Effects ◽

Sw480 Cells

Abstract Background We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects. Methods RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv. Results RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells. Conclusion The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.

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150 GAIA-102: a new class off-the-shelf allogeneic NK-like cells that can eliminate solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0150 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A163-A163

Author(s):

Yui Harada ◽

Yoshikazu Yonemitsu

Keyword(s):

Nk Cells ◽

Solid Tumors ◽

Tumor Cells ◽

Adoptive Immunotherapy ◽

Nk Cell ◽

Peritoneal Dissemination ◽

Checkpoint Inhibitors ◽

Antitumor Effects ◽

Car T

BackgroundCancer immunotherapy has been established as a new therapeutic category since the recent success of immune checkpoint inhibitors and a type of adoptive immunotherapy, namely chimeric antigen receptor-modified T cells (CAR-T). Although CAR-T demonstrated impressive clinical results, serious adverse effects (cytokine storm and on-target off-tumor toxicity) and undefined efficacy on solid tumors are important issues to be solved. We’ve developed a cutting-edge, simple, and feeder-free method to generate highly activated and expanded human NK cells from peripheral blood (US9404083, PCT/JP2019/012744, PCT/JP2020/012386), and have been conducting further investigation why our new type of NK cells, named as GAIA-102, are so effective to kill malignant cells.MethodsCryopreserved PBMCs purchased from vendors were mixed and processed by using LOVO and CliniMACS® Prodigy (automated/closed systems). CD3+ and CD34+ cells were depleted, and the cells were cultured with high concentration of hIL-2 and 5% UltraGRO® for 14 days in our original closed system. Then, we confirmed the expression of surface markers, CD107a mobilization and cell-mediated cytotoxicity against various tumor cells and normal cells with or without monoclonal antibody drugs in vitro and antitumor effects against peritoneal dissemination model using SKOV3 in vivo.ResultsImportantly, we’ve found that our GAIA-102 exhibited CD3-/CD56bright/CD57- immature phenotype that could kill various tumor cells efficiently from various origins, including Raji cells that was highly resistant to NK cell killing. More importantly, massive accumulation, retention, infiltration and sphere destruction by GAIA-102 were affected neither by myeloid-derived suppressor cells nor regulatory T-lymphocytes. GAIA-102 was also effective in vivo to murine model of peritoneal dissemination of human ovarian cancer; thus, these findings indicate that GAIA-102 has a potential to be an ‘upward compatible’ modality over CAR-T strategy, and would be a new and promising candidate for adoptive immunotherapy against solid tumors.ConclusionsWe now just started GMP/GCTP production of this new and powerful NK cells and first-in-human clinical trials in use of GAIA-102 will be initiated on 2021.Ethics ApprovalThe animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Kyushu University (approval nos. A30-234-0 and A30-359-0).

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Triacanthine exerts antitumor effects on bladder cancer in vitro and in vivo

Phytomedicine ◽

10.1016/j.phymed.2019.153069 ◽

2019 ◽

Vol 64 ◽

pp. 153069 ◽

Cited By ~ 3

Author(s):

Seung-Shick Shin ◽

Yu-Jin Park ◽

Byungdoo Hwang ◽

Sung Lyea Park ◽

Sang-Wook Han ◽

...

Keyword(s):

Bladder Cancer ◽

Antitumor Effects

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Antitumor effects of piroxicam in spontaneous canine invasive urinary bladder cancer, a relevant model of human invasive bladder cancer

Prostaglandins & Other Lipid Mediators ◽

10.1016/s0090-6980(99)90297-6 ◽

1999 ◽

Vol 59 (1-6) ◽

pp. 62

Author(s):

Deborah W. Knapp ◽

Nita W. Glickman ◽

Sulma I. Mohammed ◽

Dennis B. DeNicola ◽

William R. Widmer ◽

...

Keyword(s):

Bladder Cancer ◽

Urinary Bladder ◽

Urinary Bladder Cancer ◽

Invasive Bladder Cancer ◽

Antitumor Effects ◽

Relevant Model

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Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

Bone Research ◽

10.1038/s41413-021-00144-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Yao Fan ◽

Rongrong Zha ◽

Tomohiko Sano ◽

Xinyu Zhao ◽

Shengzhi Liu ◽

...

Keyword(s):

Brain Tumors ◽

Tumor Cells ◽

Mechanical Loading ◽

Tumor Suppression ◽

Weight Bearing ◽

Dopamine Synthesis ◽

Bone Homeostasis ◽

Antitumor Effects ◽

Simultaneous Application ◽

The Brain

AbstractMechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

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