Repetitive Dissociation from Crocidolite Asbestos Acts as Persistent Signal for Epidermal Growth Factor Receptor

Mesothelioma is an incurable form of cancer located most commonly in the pleural lining of the lungs and is associated almost exclusively with the inhalation of asbestos. The binding of asbestos to epidermal growth factor receptor (EGFR), a transmembrane signal protein, has been proposed as a trigger for downstream signaling of kinases and expression of genes involved in cell proliferation and inhibition of apoptosis. Here, we investigate the molecular binding of EGFR to crocidolite (blue asbestos; Na₂(Fe²⁺,Mg)₃Fe₂³⁺Si₈O₂₂(OH)₂) in buffer solution. Atomic force microscopy measurements revealed an attractive force of interaction (i.e., bond) as EGFR was pulled from contact with long fibers of crocidolite. The rupture force of this bond increased with loading rate. According to the Bell model, the off-rate of bond dissociation (<i>k</i>_off) for EGFR was 22 s^–1. Similar experiments with riebeckite crystals, the nonasbestiform variety of crocidolite, yielded a <i>k</i>_off of 8 s^–1. These <i>k</i>_off values on crocidolite and riebeckite are very rapid compared to published values for natural agonists of EGFR like transforming growth factor and epidermal growth factor. This suggests binding of EGFR to the surfaces of these minerals could elicit a response that is more potent than biological hormone or cytokine ligands. Signal transduction may cease for endogenous ligands due to endocytosis and subsequent degradation, and even riebeckite particles can be cleared from the lungs due to their short, equant habit. However, the fibrous habit of crocidolite leads to lifelong persistence in the lungs where aberrant, repetitious binding with EGFR may continually trigger the activation switch leading to chronic expression of genes involved in oncogenesis

Comparison of the biofilm-forming capacity of <i>S</i>. <i>aureus</i> isolates from prosthetic joint infection (PJI) and uninfected prosthetic joint (PJU) groups.

<p>Values were calculated as percentage capacity to form biofilms relative to <i>S</i>. <i>aureus</i> control strain UAMS-1. Box ends represent the 25^th and 75^th percentiles, and whisker ends represent the minimum and maximum. There was no difference in biofilm-forming capacity between isolates in the PJI and PJU groups.</p

Single Nucleotide Polymorphisms (SNPs) in fibronectin binding protein B (<i>fnbB)</i> in <i>fnbB-</i>containing isolates.

<p>*When false discovery rate control is applied, this raw p-value no longer maintains statistical significance (p = 1.00).</p><p>No SNP was associated with the prosthetic joint infected (PJI) or uninfected (PJU) isolates in the derivation cohort, external validation cohort, or late <i>S</i>. <i>aureus</i> bacteremia (SAB) group. Late SAB was defined as SAB occurring >1 year after placement or manipulation of prostheses.</p

Demographic and clinical characteristics of patients in the derivation cohort with <i>S</i>. <i>aureus</i> bacteremia and infected or uninfected prostheses.

<p>*Late infection is defined as bloodstream infection occurring >1 year after the prostheses was implanted or surgically manipulated.</p><p>Demographic and clinical characteristics of patients in the derivation cohort with <i>S</i>. <i>aureus</i> bacteremia and infected or uninfected prostheses.</p

Comparison of the fibronectin binding capacity of <i>S</i>. <i>aureus</i> isolates from prosthetic joint infection (PJI) and uninfected prosthetic joint (PJU) groups.

<p>Values were calculated as percentage capacity to bind fibronectin relative to <i>S</i>. <i>aureus</i> control strain 8325–4. Box ends represent the 25^th and 75^th percentiles, and whisker ends represent the minimum and maximum. There was no difference in fibronectin binding capacity between isolates in the PJI and PJU groups.</p

Single Nucleotide Polymorphisms (SNPs) in fibronectin binding protein A (<i>fnbA)</i> in the derivation cohort, external validation cohort, and late <i>S</i>. <i>aureus</i> bacteremia (SAB) group.

<p>*When false discovery rate control is applied, this raw p-value no longer maintains statistical significance (p = 0.22).</p><p>In the derivation cohort, no SNPs occurred with greater frequency in the prosthetic joint infection group (PJI) relative to the uninfected prosthetic joint group (PJU). In the external validation cohort, one SNP (S839N) was significantly associated with the PJU group, though when the two cohorts were combined the S839N association did not reach statistical significance (p = 0.22). Late SAB was defined as bacteremia occurring >1 year after placement or manipulation of prostheses, and here contains data from both the derivation and external validation cohorts. In the late SAB group, no SNPs occurred with greater frequency in PJI or PJU.</p

Single Nucleotide Polymorphisms (SNPs) in the binding regions (Repeats 1–11) of fibronectin binding protein B (FnBPB) in the derivation cohort (A) and the external validation cohort (B).

<p>Red boxes indicate SNPs that were only present in isolates from the prosthetic joint infection group (PJI), blue boxes indicate SNPs that were only present in the uninfected (PJU) group, and purple boxes indicate SNPs that were present in both PJI and PJU isolates.</p