Oncology General Principles Continued
Inorganic arsenic is associated with skin cancer development; increased incidence of skin cancer has been noted in individuals drinking arsenic-contaminated water.
Moreover, exposure to inorganic arsenic compounds is likely associated with excess incidence of lung cancer.
This latter exposure appears to be in the workplace setting.
The magnitude of increased risk can be seen, at least in an extreme example, in miners in Rhodesia where the primary objective is gold-mining; however, arsenic is a contaminant.
In that case, the increased likelihood of lung cancer ranged between 6-14 fold.
Arsenical pesticides, in which workers may be exposed both in manufacturing in use, also promote increased incidence of lung and skin cancer.
Ingested arsenic also exhibits a dose-response trend with respect to lung cancer risk; furthermore, this risk appeared more prominent among individuals who smoked cigarettes.
Probably lung cancer risk assessment associated with ingested arsenic should consider cigarette smoking as part of the analysis.22,23
The underlying mechanisms which might explain tumorigenic effects of arsenic remain to be fully elucidated.
Arsenic may be effective under some circumstances in treating acute promyelocytic leukemia despite arsenic being a carcinogen.
One proposed mechanism to resolve this apparent paradox was based on a finding that arsenic inhibits transcription of the hTERT gene which encodes for the reverse transcriptase subunit of human telomerase.
A reduction in telomerase enzyme activity results in chromosomal end lesions that could promote either genomic instability and carcinogenesis or cancer cell death.
Further work in this area is still required.24
Cadmium may be associated with increased likelihood of lung cancer and prostate cancer.
The primary subset of the population at risk are those who are exposed to cadmium in the workplace (e.g. battery workers and cadmium smelters).
A notable source of cadmium exposure is cigarette smoking since each pack contains about 1-2 µg cadmium.22
Cadmium itself is only weakly genotoxic; however, cadmium influences cellular activities such as proliferation, apoptosis (cell-programmed cell death) and differentiation.
Indirect mechanisms that might explain cadmium carcinogenesis include:26
Influences on gene expression and signal transduction.
Interference with cellular antioxidant systems as well as promotion of reactive oxygen species generation.
Inhibiting DNA repair and DNA methylation.
Alterations of cellular apoptosis.
Interference with E-cadherin-mediated cell-cell adhesion.
Therefore, gene induction by cadmium results in changes in cell signaling transduction pathways by means of altered protein phosphorylation states and transcription and translation factor activation.
The production of reactive oxygen species may cause increased gene expression and apoptosis.
Cadmium-induced alteration of the E-cadherin adhesion system may also promote tumor development.26
Cell-cell adhesion is typically diminished in human cancers; furthermore, this reduction appears associated with loss of “contact inhibition” of cellular proliferation.
Reduced cell-cell adhesiveness may facilitate metastasis from the primary tumor site.
The rationale is that malignant cells need to detach from the primary site, enter the circulation, eventually lodge in a vascular bed far removed perhaps from the initial site and then ultimately proliferate there.
Easier initial malignant cellular detachment from the primary tumor due to reduced cell-cell adhesion may promote this process.
The principle mediators of calcium-dependent cell-cell adhesion are categorized as members of large group of transmembrane glycoproteins, the cadherins.
Cadherins are named for "calcium-dependent adhesion."
Cadherins represent a superfamily of proteins that share cadherin represts wihch define the extracellular Ca2+-binding regions.26a,26b
One principal subtype is the E-(epithelial) cadherins.
Abnormal E-cadherin levels have been demonstrated in invasive carcinomas and carcinoma in situ.27
Increased rates of nasal cancer as well as lung cancer have been associated with occupational exposure to nickel during the refining process.
The reduction in cancer risk from nickel exposure was associated with increased environmental oversight in the industry beginning over 70 years ago; however, workers involved in nickel refining in Norway as late as the 1950s were probably at increased cancer risk.
Higher incidence of nasal, laryngeal, and lung cancer observed in that population may have resulted from concomitant exposure to smoking and nickel.22
Underlying molecular mechanisms by which nickel promotes cancer continue to be the subject of investigation.
One possibility is that nickel binds to cell nuclear histones.28
Nickel appears to damage, selectively, heterochromatin. (Heterochromatin is a densely-stained chromosomal region.)
These regions tend to remain tightly coiled (and darkly staining) throughout the cellular cycle.]
A principal effect of nickel may be to reduce gene expression near heterochromatin by causing a loss of histone H4 and H3 acetylation as well as reduced DNA hypermethylation.
Furthermore, soluble nickel ions, interacting with cell surface receptors, may activate cell signaling promoting cellular gene induction.29
Histones (5 types) are proteins commonly found in chromosomes.
They bind to DNA and form a "scaffolding" around which DNA winds, thus forming chromatin structure.
Histones, being rich in the amino acids arginine and lysine, are basic proteins and are involved in controlling gene activity.
Chromate: Hexavalent (Cr(VI)) (not trivalent) chromium exposure causes cancer both in humans and in mammalian cells in vitro31. Increased lung cancer risk has been noted both in chromate production plants in England (300%) and in Baltimore (200%).22
Chromium VI carcinogenicity probably involves particulate forms of limited solubility. Cr(VI) oxyanions move across the cell membrane by means of a non-specific anionic transporter.
Cr(VI) is metabolized, reductively, by reactions involving ascorbic acid, glutathione (GSH) and cysteine (Cys).
During this reductive process, “genetic lesions” are formed, including:
Cr-DNA binary (mono) adducts
Cr-DNA ternary adducts
DNA protein cross-link
bi-functional adducts (DNA interstrand cross-links adducts)
single-strand breaks and
Interstrand cross-links could result in apoptosis (cell death) or terminal growth stoppage because of physical barriers to DNA replication and/or transcription. Ternary DNA adducts might be pre-mutagenic.32
The predisposition of asbestosis patients to lung cancer has been described for over 70 years.
Lung cancer induced by asbestos exposure is associated with a long latency period.
Mesothelioma of the lung appears a specific consequence of asbestos exposure.
Subpopulations of the workforce predisposed to asbestos-induced mesothelioma include those working in insulation workers as well as asbestos manufacturing workers and others.22
Asbestos references a number of naturally occurring hydrated mineral silicate fibers which are causative of certain pulmonary and pleural diseases.
There are two major groups of asbestos:
(1) serpentine of which chrysotile is the representative form and
(2) amphibole represented by crocidolite, anthophyllite, amosite and tremolite.
Of these, crocidolite is the most oncogenic asbestos type involved in causing malignant mesothelioma (MM).
Malignant mesothelioma targets the serosal lining of the plural, peritoneal and pericardial cavities and the disease causes about 2500 mortalities per year in the United States.
The mechanism by which asbestos causes cancer remains to be elucidated.34
The following represents one pathologic model: 34
(1) Crocidolite, pictured above. exposure promotes macrophage accumulation in plural cavities and in the lung.
(2) Macrophages upon interacting with crocidolite releases TNF-α (tumor necrosis factor alpha); concurrently asbestos causes primary human mesothelial cells (HM) to secrete TNF-α (i.e. both paracrine and autocrine affects).
(3) TNF-α activates NF-κB [nuclear factor-kappa B, a protein complex functioning as a transcription factor with broad genetic regulatory activities].
This protein family, consisting of structurally-similar transcription factors, is involved in regulation of immune responses, inflammatory responses, apoptosis, cellular growth and developmental processes.35
Furthermore, NF-κB appear active in many disease states, not just cancer, including asthma, heart disease, neurodegenerative disorders and others.
TNF-α, a proinflammatory cytokine, not only induces NF-κB, but affects oncogenesis because NF-κB is an important regulator of oncogenesis.
Often cell survival is enhanced due to NF-κB activation, since NF-κB activation itself both increases cell proliferation while inhibiting apotosis (programmed cell death).
(4) These effects permit human mesothelial cells (HM) with asbestos-caused DNA damage to divide rather than die.
Consequently, with sufficient accumulation of DNA damage, malignant mesothelioma could develop.
Silica Silica dust exposure in the occupational setting predisposes to enhanced lung cancer risk. Individuals involved in the production of ceramic plumbing would be in such a risk category.36 The principal human exposure silica form is usually quartz, cristobalite and tridymite. Construction, sandblasting, foundries, granite quarrying and processing as well as ceramic industries represent sites for occupational exposure. In terms of dimension, inhalation of crystalline silica suggest particle sizes of about 2-5 µm. From a mechanistic point of view, at least superficially similar to what has been described for asbestos, a pro-inflammatory effect of crystalline silica (quartz) appears involved in lung cancer development, at least in rats. Furthermore, epithelial proliferation is also involved.37 In cell culture, neoplastic transformation by crystalline silica as well as chromosomal damage have been observed. In aqueous media, crystalline silica promotes oxygen free radical production; furthermore, direct binding of crystalline silica to DNA, as assayed by infrared spectrometry, has been noted. These types of studies suggest that silica carcinogenesis might involve DNA binding of silica, thus exposing DNA sites to the damaging effects of oxygen free radicals.39
Wood Dust: An increased risk of nasal carcinomas is likely associated with exposure to wood dust in a cell population of workers exposed and furniture manufacturing. Hardwood dusts appear associated with highest risk. Slight increases in risks of other cancers such as lung cancer, Hodgkin's disease and laryngeal cancer may also accompany wood dust occupational exposure.36
Although increased risk for human sinonasal cancer (SNC) due to wood dust exposure has been well documented by epidemiological analysis, the underlying mechanism remains to be determined. Increased COX-2 levels have been found in malignant and premalignant tissues and COX-2 may be linked to cancer development. COX-2 expression appears associated with wood dust occupational exposure. This work suggested that this increased COX-2 expression indicated an inflammatory role in sinonasal carcinogenesis.40
COX-2 is an abbreviation for cycloxygenase-2, an enzyme, which catalyzes prostaglandin production. Specifically, COX-1 and COX-2 convert arachidonic acid to prostaglandin endoperoxide.
COX-1 (PGH synthase-1) is continuously (constitutively) expressed; however, COX-2 (PGH synthase-2) is inducible. COX-2 is categorized as an immediate early-response gene product that is up-regulated (increased in expression) by a number of factors including tumor promoters, cytokines, growth factors, and shear stress as might occur in vascular walls. COX-2 activity promotes prostanoid formation associated with inflammation and cancer. Examples of prostanoids include prostaglandins, prostacyclin, and thromboxane.41
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