Apoptosis In Primary Tumors Research Articles

Selective Manipulation of the Mitochondria Oxidative Stress in Different Cells Using Intelligent Mesoporous Silica Nanoparticles to Activate On-Demand Immunotherapy for Cancer Treatment.

Herein, the vitamin K2 (VK2)/maleimide (MA) coloaded mesoporous silica nanoparticles (MSNs), functional molecules including folic acid (FA)/triphenylphosphine (TPP)/tetrapotassium hexacyanoferrate trihydrate (THT), as well as CaCO3 are explored to fabricate a core-shell-corona nanoparticle (VMMFTTC) for on-demand anti-tumor immunotherapy. After application, the tumor-specific acidic environment first decomposed CaCO3 corona, which significantly levitates the pH value of tumor tissue to convert M2 type macrophage to the antitumor M1 type. The resulting VMMFTT would then internalize in both tumor cells and macrophages via FA-assisted endocytosis and free endocytosis, respectively. These distinct processes generate different amount of VMMFTT in above two cells followed by 1) TPP-induced accumulation in the mitochondria, 2) THT-mediated effective capture of various signal ions to cut off signal transmission and further inhibit glutathione (GSH) generation, 3) ions catalyzed reactive oxygen species (ROS) production through Fenton reaction, 4) sustained release of VK2 and MA to further enhance the ROS production and GSH depletion, which caused significant apoptosis of tumor cells and additional M2-to-M1 macrophage polarization via different processes of oxidative stress. Moreover, the primary tumor apoptosis further matures surrounding immature dendritic cells and activates T cells to continuously promote the antitumor immunotherapy.

Chloroquine Inhibition of Autophagy Enhanced the Anticancer Effects of Listeria monocytogenes in Melanoma

Listeria monocytogenes has been shown to exhibit antitumor effects. However, the mechanism remains unclear. Autophagy is a cellular catabolic process that mediates the degradation of unfolded proteins and damaged organelles in the cytosol, which is a double-edged sword in tumorigenesis and treatment outcome. Tumor cells display lower levels of basal autophagic activity than normal cells. This study examined the role and molecular mechanism of autophagy in the antitumor effects induced by LM, as well as the combined antitumor effect of LM and the autophagy inhibitor chloroquine (CQ). We investigated LM-induced autophagy in B16F10 melanoma cells by real-time PCR, immunofluorescence, Western blotting, and transmission electron microscopy and found that autophagic markers were increased following the infection of tumor cells with LM. The autophagy pathway in B16F10 cells was blocked with the pharmacological autophagy inhibitor chloroquine, which led to a significant increase in intracellular bacterial multiplication in tumor cells. The combination of CQ and LM enhanced LM-mediated cancer cell death and apoptosis compared with LM infection alone. Furthermore, the combination of LM and CQ significantly inhibited tumor growth and prolonged the survival time of mice in vivo, which was associated with the increased colonization and accumulation of LM and induced more cell apoptosis in primary tumors. The data indicated that the inhibition of autophagy by CQ enhanced LM-mediated antitumor activity in vitro and in vivo and provided a novel strategy to improving the anticancer efficacy of bacterial treatment.

Effect of serpinE1 overexpression on the primary tumor and lymph node, and lung metastases in head and neck squamous cell carcinoma.

Serpin Family E Member 1 (SerpinE1) overexpression associates with poor clinical outcome in head and neck squamous cell carcinoma (HNSCC) patients. This study analyzed the role of serpinE1 in HNSCC dissemination. We studied the phenotypic characteristics and dissemination of HNSCC cells overexpressing serpinE1 using an orthotopic model and the association between serpinE1 overexpression and clinicopathological variables in patients included in The Cancer Genome Atlas database. SerpinE1 overexpression increased proliferation, tumor budding, and the stromal component, while inhibiting apoptosis in primary tumors. It also enhanced the affectation and metastatic growth in lymph nodes, and the dispersion and growth of metastatic foci in the lung. High serpinE1 expression was associated with larger tumor size, undifferentiated tumors, lymph node metastasis, extracapsular spread, and the presence of perineural and angiolymphatic invasion. SerpinE1 overexpression promotes tumor aggressiveness and metastatic dissemination to lymph nodes and lung consistently with its association with poor outcome in HNSCC patients.

Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression

The downregulation of receptor tyrosine kinase EphA7 is frequent in epithelial cancers and linked to tumor progression. However, the detailed mechanism of EphA7-mediated prostate tumor progression remains elusive. To test the role of EphA7 receptor in prostate cancer (PCa) progression directly, we generated EphA7 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its phosphorylation by site-directed mutagenesis. Overexpression of wild-type (WT) EphA7 in PCa cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, ectopic expression of WT EphA7 both can delay PCa cell proliferation and could inhibit PCa cell migration and invasion. This protein can also induce PCa cell apoptosis that correlated with increasing the protein expression levels of Bax, elevating the caspase-3 activities, reducing the protein expression levels of Bcl-2 and facilitating the dephosphorylation of Akt, which is further increased by the stimulation of ephrinA5-Fc. However, expression of these EphA7 mutants in PCa cells has no effect in vivo and in vitro. The expression of EphA7 and ephrinA5 was significantly decreased in PCa specimens compared with BPH tissues or paired normal tissues. Moreover, the phosphorylation of EphA7 was positively related with ephrinA5 expression in human prostate tissues. In sum, receptor phosphorylation of EphA7, at least in part, suppress PCa tumor malignancy through targeting PI3K/Akt signaling pathways.

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligand-induced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

Primary Apoptosis as a Prognostic Index for the Classification of Metastatic Renal Cell Carcinoma

We identified novel biological markers of prognosis in primary histopathological specimens from patients with metastatic renal cell carcinoma. Apoptotic indexes (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling), proliferation rates (Ki-67 antigen), p21 (WAF1/cip1) expression and CD95 (APO-1/Fas) expression were determined in paraffin embedded nephrectomy specimens from 73 patients with histologically confirmed, progressive metastatic disease. Kaplan-Meier survival analysis, log rank statistics and 2-proportional Cox regression analysis were done to identify new risk factors in addition to conventional classification criteria, and demonstrate statistical independence. Multivariate analysis indicated that primary tumor apoptosis (p = 0.0116) and the interval from diagnosis to metastatic disease (p = 0.002) had a high predictive impact on overall survival after initial diagnosis. Patients were assigned to 2 risk groups, namely a poor prognosis group with a median survival of 20 months, defined by apoptosis less than 6% in the primary tumor nephrectomy specimen and a time from initial diagnosis to metastatic disease of less than 6 months, and a good prognosis group with a median survival of 56 months, defined as the absence of 1 or 2 risk factors. Our findings showed that primary tumor apoptosis is a novel independent predictor in patients with metastatic renal cell carcinoma at initial diagnosis. It leads to a new prognostic index in the pretreatment classification of metastatic renal cell carcinoma.

Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

Microsatellite instability is associated with the loss of apoptosis in ductal breast carcinomas.

Metastatic progression in ductal breast carcinomas are related to apoptosis in primary tumors. Frameshift mutations in a single-repeat sequence within the coding region (G)8 of the pro-apoptotic Bax gene have been related to microsatellite instability (MSI) and progression of some carcinomas and lymphomas. The aim of this study was to explore whether the extended lifespan of breast cancer cells can also be triggered by Bax mutation in ductal-breast carcinomas, and whether breast cancer cell MSI is related to the loss of apoptosis. For this purpose we studied frameshift mutations of a microsatellite (G)8 in the third exon of the Bax gene in a series of 105 ductal breast carcinomas, at T1 and T2-3 stages, 45 of which had lymph node metastasis. We analyzed MSI in five sequences of DNA isolated from normal and tumor tissue samples taken from 86 patients, and we explored the relationship between MSI and tumor apoptosis status. Bax mutation was not present in ductal breast carcinomas. MSI (two or more markers altered) was detected in 11.6% of tumors. Loss of apoptosis occurred in 80% (8/10) tumors with MSI, versus 17.8% of tumors without MSI (chi2 test, p = 0.0004), independently of Bax protein expression. We conclude that frameshift mutations of a microsatellite (G)8 of the Bax gene are not critical for the loss of apoptosis in breast cancer, and that loss of apoptosis may be a consequence of overexpression of anti-apoptotic protein Bcl-2 or Bcl-xL. Moreover, MSI in breast carcinomas might be the cause of loss of an apoptotic pathway that is not induced by frameshift mutations of a microsatellite (G)8 of the Bax gene.