Interactions of asbestos-activated macrophages with an experimental fibrosarcoma

Supernatants from in vivo asbestos-activated macrophages failed to show any cytostatic activity against a syngeneic fibrosarcoma cell line in vitro. UICC chrysotile-induced peritoneal exudate cells also failed to demonstrate any growth inhibitory effect on the same cells in Winn assays of tumor growth. Mixing UICC crocidolite with inoculated tumor cells resulted in a dose-dependent inhibition of tumor growth; this could, however, be explained by a direct cytostatic effect on the tumor cells of high doses of crocidolite, which was observed in vitro

Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1)

Abstract VEGF signaling through its tyrosine kinase receptor, VEGFR2 (FLK1), is critical for tumor angiogenesis. Previous studies have identified a critical gene dosage effect of VegfA in embryonic development and vessel homeostasis, neovascularization, and tumor growth, and potent inhibitors of VEGFR2 have been used to treat a variety of cancers. Inhibition of FGFR signaling has also been considered as an antiangiogenic approach to treat a variety of cancers. Inhibition of VEGFR2 with neutralizing antibodies or with pharmacological inhibitors of the VEGFR tyrosine kinase domain has at least short-term efficacy with some cancers; however, also affects vessel homeostasis, leading to adverse complications. We investigate gene dosage effects of Vegfr2, Fgfr1, and Fgfr2 in three independent mouse models of tumorigenesis: two-stage skin chemical carcinogenesis, and sub-cutaneous transplantation of B16F0 melanoma and Lewis Lung Carcinoma (LLC). Mice heterozygous for Vegfr2 display profound defects in supporting tumor growth and angiogenesis. Unexpectedly, additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice shows similar tumor growth and angiogenesis as the Vegfr2 heterozygous mice. Notably, hematopoietic deletion of two alleles of Vegfr2 had minimal impact on tumor growth, with little effect on angiogenesis, reinforcing the importance of endothelial Vegfr2 heterozygosity. These studies reveal previously unrecognized Vegfr2 gene dosage effects in tumor angiogenesis and a lack of synergy between VEGFR2 and endothelial FGFR1/2 signaling during tumor growth

New molecular mediators in tumor angiogenesis

Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition

Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.Fil: Chiarella, Paula. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vermeulen, Mónica. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Montagna, Daniela R.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vallecorsa, Pablo. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Strazza, Ariel Ramiro. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Bustuoabad, Oscar D.. Retired; ArgentinaFil: Ruggiero, Raúl A.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Prehn, Richmond T.. University Of Washington, Seattle

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4’-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC

Frondoside A suppressive effects on lung cancer survival, tumor growth, angiogenesis, invasion, and metastasis

A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 mu M of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 mu M) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer

PPAR-alpha: a novel target in pancreatic cancer

Background: Current targeted therapies in pancreatic cancer have been ineffective. The tumor stroma, including intra- and peri-tumoral inflammation and fibrosis, is increasingly implicated in pancreatic cancer. Pancreatic cancer is characterized by a highly fibrotic tumor environment resulting in stromal resistance to chemotherapy. Peroxisome proliferator-activated receptor-alpha (PPARα), a ligand-activated nuclear receptor/transcription factor, is a negative regulator of inflammation. In PPARα deficient mice, stromal processes inhibit tumor growth, resulting in dormant tumors. The presence of PPARα in the tumor cells as well as in the host is necessary for unabated tumor growth. Objective: We hypothesized that blocking the PPARα pathway with a small molecule PPARα antagonist (NXT) may prevent pancreatic cancer progression by targeting tumor cells as well as non-neoplastic cells in the tumor microenvironment. Methods: Growth inhibitory activity of the PPARα antagonist was assessed in murine as well as human pancreatic tumor cell lines (Panc0H7 and BxPC3) and in a murine macrophage cell line (RAW 264.7). Cell viability was determined by trypan blue exclusion assay. AKT, P-AKT, PCNA, BAX, and p27 levels were analyzed by western blot analysis. Cell cycle changes were detected by flow cytometry. Cellular senescence was determined by senescence-associated β-gal (SA-β-gal) staining. Results: The PPARα antagonist inhibited cell growth in macrophages and in pancreatic tumor cells as confirmed by reduced protein level expression of PCNA and activated AKT. Treatment of the PPARα antagonist was non-cytotoxic to tumor cells. Inhibition of PPARα induced cell cycle arrest at G0/G1 in tumor cells and macrophages. The induction of cellular senescence was observed in pancreatic cancer cells. Interestingly, we observed a reduction in protein level expression of BAX, a marker for apoptosis, and p27, an inhibitor of the cell cycle. Conclusion: We now demonstrate that a PPARα antagonist exerts its anti-growth activity by inducing G0/G1 cell cycle arrest, thereby inducing cellular senescence without cell death. These findings provide a mechanism for the anti-tumorigenic activity of PPARα inhibition, and the rationale to use PPARα antagonists as a novel therapeutic approach to pancreatic cancer.2016-11-03T00:00:00

Cancer prevention and therapy through the modulation of the tumor microenvironment

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer

Targeting tachykinin receptors in neuroblastoma

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma