The Relationship between tumor blood flow, angiogenesis, tumor hypoxia, and aerobic glycolysis

23rd Thursday, 2014  |   Uncategorized  |  no comments

tumor

Anaerobic glycolysis is the transformation of glucose to pyruvate when limited amounts of oxygen (O2) are available. persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.

The survival of cancer cells is contingent on their supply of oxygen and nutrients such as glucose via the bloodstream. The establishment and growth of malignant tumors are, therefore, critically dependent on their ability to stimulate the formation of new blood vessels (angiogenesis) to support their metabolic needs

Antiangiogenic therapies are being pursued as a means of starving tumors of their energy supply. Although numerous studies show that such therapies render tumors hypoxic, just as many studies have, surprisingly, shown improved tumor oxygenation. These contradicting findings challenge both the original rationale for antiangiogenic therapy and our understanding of the physiology of tissue oxygenation. The flow–diffusion equation, which describes the relation between blood flow and the extraction of freely diffusible molecules in tissue, was recently extended to take the heterogeneity of capillary transit times (CTH) into account. CTH is likely to be high in the chaotic microvasculature of a tumor, increasing the effective shunting of blood through its capillary bed. We review the properties of the extended flow–diffusion equation in tumor tissue. Elevated CTH reduces the extraction of oxygen, glucose, and cytotoxic molecules. The extent to which their net extraction is improved by antiangiogenic therapy, in turn, depends on the extent to which CTH is normalized by the treatment. The extraction of oxygen and glucose are affected to different extents by elevated CTH, and the degree of aerobic glycolysis—known as the Warburg effect—is thus predicted to represent an adaptation to the CTH of the local microvasculature.

Source

Østergaard L, Tietze A, Nielsen T, et al. Cancer Res September 15, 2013 73; 5618. doi: 10.1158/0008-5472.CAN-13-0964

 

 

Genistein from soy inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells

20th Monday, 2014  |   Uncategorized  |  no comments

0089_soy_bean

Genistein (Gen) exhibits anti-mutagenic and anti-metastatic activities in hepatoma cell lines. Gen has suppressive effects on tumor growth and angiogenesis in nude mice. Gen suppresses the enzymatic activity of matrix metalloproteinase (MMP)-9; however, the mechanism underlying its anti-invasive activity on hepatocellular carcinoma (HCC) cells is unclear.

In this study, the possible mechanisms underlying Gen-mediated reduction of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2) were investigated.
Gen suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-kappa B (NF-kappaB) activity. Gen suppressed TPA-induced AP-1 activity through inhibitory phosphorylation of extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and TPA-stimulated inhibition of NF-kappaB nuclear translocation through IkappaB inhibitory signaling pathways. Moreover, Gen suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-kappaB and AP-1.

Gen and its inhibition of multiple signal transduction pathways can control the invasiveness and metastatic potential of HCC. 
Source

Wang S-D, Chen B-C, Kao S-T, Liu C-J, Yeh C-C. BMC Complementary and Alternative Medicine 2014, 14:26  doi:10.1186/1472-6882-14-26

Inhibitory and cytotoxic activities of salvia officinalis L. Extract on human lymphoma and leukemia cells by induction of apoptosis.

6th Monday, 2014  |   Uncategorized  |  no comments

PastedGraphic-2

Salvia officinalis L., also known as Maryam Goli, is one of the native plants used to Persian medicinal herbs. Zare Shahneh et al., (2013) examined the in vitro cytotoxic activities of a standardized crude methanol extracts prepared from Salvia officinalis L., on a non-Hodgkin’s B-cell lymphoma (Raji) and human leukemic monocyte lymphoma (U937), Human acute myelocytic leukemia (KG-1A) and Human Umbilical Vein Endothelial (HUVEC) cell lines. 

The effect of methanolic extract on the inhibition of cell proliferation and cytotoxic activity was evaluated by Dye exclusion and Micro culture tetrazolium test (MTT) cytotoxicity assay. Cell death ELISA was employed to quantify the nucleosome production result from nuclear DNA fragmentation during apoptosis and determined whether the mechanism involves induction of apoptosis or necrosis. 

The present results demonstrated that methanolic extract at 50 to 800 ?g/ml dose and time-dependently suppressed the proliferation of KG-1A, U937 and Raji cells by more than 80% (p<0.01), with ascending order of IC50 values in 24: KG-1A (214.377 ?g/ml), U937 (229.312 ?g/ml) and Raji (239.692 ?g/ml) when compared with a chemotherapeutic anticancer drug, paclitaxel (Toxol), confirming the tumour-selective cytotoxicity. The crude extract however did not exert any significant cytotoxic effect on normal cell line HUVEC (IC50>800 Ag/ml). Nucleosome productions in KG-1A, Raji and U937 cells were significantly increased respectively upon the treatment of Salvia officinalis L. extract. 

The Salvia officinalis L. extract was found dose and time-dependently inhibits the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway. 

Source
Zare Shahneh F, Valiyari S, Baradaran B, et al. (2013) Adv Pharm Bull. 2013;3(1):51-5. doi: 10.5681/apb.2013.009. 

Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3.

6th Monday, 2014  |   Uncategorized  |  no comments

Ursolic-Acid

Wong et al., have previously reported Signal Transducer and Activator of Transcription 3 (STAT3) to be constitutively activated in aldehyde dehydrogenase (ALDH)(+)/cluster of differentiation-133 (CD133)(+) colon cancer-initiating cells. In the present study they tested the efficacy of inhibiting STAT3 signaling in human colon cancer-initiating cells by ursolic acid (UA), which exists widely in fruits and herbs.

Their data demonstrated that UA inhibited STAT3 phosphorylation, and induced caspase-3 cleavage of ALDH(+)/CD133(+) colon cancer-initiating cells. UA also reduced cell viability and inhibited tumor sphere formation of colon cancer-initiating cells, more potently than two other natural compounds, resveratrol and capsaicin. UA also inhibited the activation of STAT3 induced by interleukin-6 in DLD-1 colon cancer cells. Furthermore, daily administration of UA suppressed HCT116 tumor growth in mice in vivo.

Their results suggest STAT3 to be a target for colon cancer prevention. UA, a dietary agent, might offer an effective approach for colorectal carcinoma prevention by inhibiting persistently activated STAT3 in cancer stem cells.

Source Wang W, Zhao C, Jou D, Lü J, Zhang C, Lin L, Lin J. Anticancer Res. 2013 Oct;33(10):4279-84.

No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period

3rd Tuesday, 2013  |   Prostate Cancer  |  no comments

The below report suggests survival rates have not improved and no consistent improvement in overall or disease-specific survival in PCa due to PSA screening. Remember elevated PSA is not an indication of cancer but a sign of inflammation or sexual activity. The on going opinion is that sex and ejaculations before the blood draw can cause the prostate to produce more PSA and therefore give a false positive.

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No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period

Prostate cancer mortality in the United States has declined by nearly 40% over the last 25 years. However, to the authors’ knowledge, the contribution of prostate-specific antigen (PSA) screening for the early detection of prostate cancer remains unclear and controversial. In the current study, the authors attempted to determine whether improvements in survival over time among patients with metastatic prostate cancer have contributed to the decline in mortality. 

Men aged ≥ 45 years who presented with de novo metastatic prostate cancer from 1988 to 2009 were identified within the California Cancer Registry. Overall survival and disease-specific survival were estimated using the Kaplan-Meier method. A multivariate analysis with Cox proportional hazards modeling was performed to adjust for different distributions of variables between groups.

A total of 19,336 men presented with de novo metastatic prostate cancer during the study period. On multivariate analysis, overall survival was found to be better for men diagnosed from 1988 through 1992 and 1993 through 1998 than for men diagnosed in the most recent era (hazards ratio, 0.78; 95% confidence interval, 0.72-0.85 [P < .001] and HR, 0.79; 95% confidence interval, 0.74-0.86 [P < .001]). There was no improvement in disease-specific survival observed when comparing the most contemporary men (those diagnosed between 2004 and 2009) with those diagnosed between 1988 and 1997.

In this analysis of men presenting with de novo metastatic prostate cancer, no consistent improvement in overall or disease-specific survival could be demonstrated over time. These data suggest that improvements in survival for patients with advanced disease have not contributed substantially to the observed drop in prostate cancer mortality over the PSA era and that stage migration secondary to PSA screening plays a more prominent role.

Source

Wu , J.N., et al. Cancer (Nov 2013) DOI: 10.1002/cncr.28485

 
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