In communities which depend on Beta-carotene producing food staples ( " Foods rich in beta-carotene include orange fruits and vegetables such as apricots, cantaloupes, and carrots, as well as leafy green vegetables such as broccoli,spinach " etc..) and water supplies lacking iron, the combination of plenty antioxidants and iron deficiency could potentially be a problems particularly for women. Women in these regions are at increased risk of being Iron deficient because of Menses (Versus Men) and therefore could be at higher risk of developing "non smoker" type of lung cancers.
We are trying to look into this issue because a simple Iron monitoring of serum level of iron could reverse the the trend of lung cancer occurrence in these region. We should confess that Zinc level could have an impact as it goes hand in hand with Iron level as demonstrated in many studies.
Scientific basis of this suspicion
======================
"Recent studies have shed light on the mechanisms of hypoxia-driven stabilization of HIF-1α protein. Under normal oxygen tension, HIF-1α protein is hydroxylated on two proline residues by a family of oxygen-dependent prolyl hydroxylases (PHD1–3), and the modified HIF-1α becomes a substrate for polyubiquitination by a protein complex containing von Hippel-Lindau proteins (pVHL) and is thus targeted for degradation [1]. The enzymatic activities of PHD proteins are sensitive to oxygen availability. Under low-oxygen conditions, PHD proteins are unable to modify the HIF-1α protein, keeping HIF-1α protein unhydroxylated and allowing it to escape pVHL recognition and subsequent degradation, resulting in the triggering of the hypoxia responses [2]. HIF-1α protein is usually degraded under normal oxygen concentrations (normoxia), but in hypoxic conditions or in the presence of iron chelators, the degradation rate decreases, and HIF-1α protein accumulates and associates with HIF-1β to form a functional transcription complex, triggering the transcription of a host of hypoxia-inducible genes.
HIF-1α protein stabilization, however, is not limited to hypoxic conditions, and the so-called hypoxia responses can occur even with an adequate oxygen supply. This oxygen tension-independent hypoxia response can result from a wide range of possible genetic alterations and signaling malfunctions, including loss of VHL [3], p53 [4], or PTEN (a phosphatidylinositol trisphosphate lipid phosphatase) [5]; or activation of phosphatidylinositol 3-kinase/Akt [6] or Src pathways [7]. Hypoxia-independent HIF-1α protein stabilization is seen in patients with von Hippel-Lindau disease, a genetic disease in which one copy of the VHL gene is either inactivated or deleted. In these patients, when the remaining normal copy of the VHL gene is lost or inactivated, the HIF transcriptional complexes stay constitutively active, even under normal oxygen concentrations, due to faulty, pVHL-dependent degradation pathways. This dysregulated hypoxia pathway is a key factor in the development of multiple neoplasms in patients with von Hippel-Lindau disease [8]. CHI et al!"
You read correctly, in the "presence of iron Chelators" means iron deficiency.
And Iron deficiency is again worse in women who have menses ! The length of exposure to menses is increased in communities with "one child policy" since natural amenorrhea associated with child bearing is minimal in these society presumably. Rates of abortions may also play into the amount of iron deficiency in women in these regions. Length of the iron deficiency state and prolong exposure to antioxidants appear critical. So, iron deficiency will "protect" HIF-1 alpha protein from Ubiquitin dependent degradation and drive its association with HIF-1beta leading to stimulation or activation of transcription factors, MAPK pathways, and dangerous heterogeneic types of genes in the families of Rho, and Src. The direct involvement of the Estrogen cannot be discounted since Estrogen Receptors have been found activated in lung cancer tissue! Again give weight to the observation that it is indeed non smoker women are indeed the target of this disease.
FURTHER SUPPORTIVE EVIDENCES
======================
The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.
Source
Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. jtabernero@vhebron.netAbstract
Multiple
cellular pathways influence the growth and metastatic potential of
tumors. This creates heterogeneity, redundancy, and the potential for
tumors to bypass signaling pathway blockade, resulting in primary or
acquired resistance. Combining therapies that inhibit different
signaling pathways has the potential to be more effective than
inhibition of a single pathway and to overcome tumor resistance.
Vascular endothelial growth factor (VEGF) and epidermal growth factor
receptor (EGFR) inhibitors have become key therapies in several tumor
types. Close relationships between these factors exist: VEGF signaling
is up-regulated by EGFR expression and, conversely, VEGF up-regulation
independent of EGFR signaling seems to contribute to resistance to EGFR
inhibition. Therefore, inhibition of both pathways could improve
antitumor efficacy and overcome resistance to EGFR inhibition.
Preclinical studies have shown that VEGF and EGFR inhibitors can have
additive effects and that combined inhibition is effective in EGFR
inhibitor-resistant cell lines. Clinical trials have also produced
promising data: combining the anti-VEGF monoclonal antibody bevacizumab
with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase
inhibitor erlotinib increases benefit compared with either of these
anti-EGFR agents alone or combined with chemotherapy. The potential of
this novel approach to anticancer therapy will be elucidated by large,
ongoing clinical trials.
. No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.
Effect of iron supplementation on oxidative stress and antioxidant status in iron-deficiency anemia.
Source
Department of Hematology, Medical School, Selcuk University, Konya, Turkey.Abstract
The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.
Source
Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. jtabernero@vhebron.netAbstract
Multiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, redundancy, and the potential for tumors to bypass signaling pathway blockade, resulting in primary or acquired resistance. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have become key therapies in several tumor types. Close relationships between these factors exist: VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor-resistant cell lines. Clinical trials have also produced promising data: combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The potential of this novel approach to anticancer therapy will be elucidated by large, ongoing clinical trials.. No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.
AND WE THANK RESEARCHERS QUOTED HERE FOR THEIR CONTRIBUTIONS!
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CLEARLY IT DOES NOT TAKE A GENIUS TO SEE THE POTENTIAL THREAD OF ASSOCIATION
Iron deficiency (and possibly Zinc amount or serum levels) could have a role. Remember Sirtuins and Butein uses in these regions are also increased. Src and related membrane located molecules have special sites of attachment for Iron. And level of iron affect deeply these molecule. The gene activator Erythropoietin is indeed here also!
one of the gene activated is VEGF which a complicated dance with EGFR. In some conditions, VEGF inhibits EGFR, in other it drive the activation of EGFR. And EGFR expression is peculiar in this disease, so much so that it would be illegal no to consider anti -EGFR as first line treatment in this disease!
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