Chapter 11 Chemicals and Cancer Chemicals and Cancer

Chapter 11: Chemicals and Cancer

Chemicals and Cancer • The etiology and pathophysiology of cancer is extremely complex. – Cancer is a collection of diseases that share common aspects of cellular pathophysiology. – Cells may lose the normal regulatory control mechanisms that keep growth and replication in check with each other.

Chemicals and Cancer, cont. • In the absence of regulatory controls, chaos ensues. • Although cancerous cells are clearly abnormal by all measures of physiology, biochemistry, and behavior, other patterns of growth are recognized to be associated with changes in normal cellular physiology.

Chemicals and Cancer, cont. • Hyperplastic growth results in the production of more cells than one would expect to see in a particular tissue. – Pregnancy induces hormone-dependent hyperplasia in the breast. – The end of gestation and cessation of lactation return the tissue to its normal state.

Chemicals and Cancer, cont. • Metaplasia refers to a change in growth that is not necessarily concomitant with a change in mass. – It can be induced environmentally. – The columnar ciliated respiratory epithelia of the airways, for example, can become nonciliated and squamous from smoking. – The epithelia may revert over time back to the normal ciliated morphology given enough time away from cigarettes and depending on the extent of the exposure.

Chemicals and Cancer, cont. • Unlike metaplasia and hyperplasia, neoplastic growth generally persists or progresses.

Genomics • Over the last decade a revolution in our understanding of genetics has occurred, giving rise to an area of study called genomics. Genomics studies individual genes and multiple gene interactions and the effect of environmental stressors on them.

Genomics, cont. • The importance of this has led to the formation of the Centers for Disease Control and Prevention (CDC) Office of Genomics. In 2004 the CDC and Institute of Medicine formed a Committee on Genomics and the Public Health in the 21 st Century, which included experts in the fields of genetics, public health law, toxicology and pharmacology, health care delivery, and others. – The following topics were included in the discussions: • • Bridging genomics and public health Genomics as a science The clinical use of genomic information Gene–environment interactions

Neoplasms or Tumors • The chemical mutations have additionally been shown to be associated with many forms of neoplasms or tumors. Some clarification of these and other commonly used terms may be necessary: – Tumor: A mass of cells whose growth is atypical when referenced to the normal surrounding tissue structure. – Neoplasm: Literally means “new growth” and is a term commonly used the same way that the term tumor is used. – New formation: A mass whose growth is incoordinate with the surrounding normal tissue and that persists in the absence of an inciting stimulus.

Neoplasms or Tumors: Definitions continued – Benign tumor: A noncancerous tumor or growth that remains confined to the growth site and may increase in size over time but does not invade into distant tissues. – Malignant tumor: Any cancerous tumor that may, depending on the type of cancer, spread from its primary growth site to potentially distant sites by its ability to metastasize. – Cancer: The general term to designate any tumor or cells that have departed far from what is recognized as normal with respect to structure, growth, and replication.

Mutations & Cancer Development

Mutations in Genes That Regulate Cell Growth and Differentiation • Oncogenes – Oncogenes are mutated forms of protooncogenes. • Tumor Suppressor Genes – These genes are sometimes referred to as antioncogenes.

Oncogenes • Oncogenes are mutated forms of proto-oncogenes. • Proto-oncogenes are the normal regulatory genes that code for cellular growth factors, chemical messengers, and other cellular mediators that orchestrate growth and differentiation. • There are more than 100 different oncogenes whose products include: – – – Growth factors Receptors Cytoplasmic kinases Survival proteins Transcription factors Other proteins for signal transduction

Tumor Suppressor Genes • Tumor suppressor genes play an important role in maintaining a balance in the response of the cell to positive and negative regulators of cellular growth. • The gene codes for: – – – Inducers of differentiation Cell adhesion molecules Inhibitors of cellular proliferation Transcription factors Inhibitors of angiogenesis

Tumor Suppressor Genes, cont. • The importance of the tumor suppressor gene is to limit the proliferation of mutated cells. • Malfunction may be an increased risk factor for cancer development and is supported by observations in humans where there is a family history of certain types of cancers, that is, a mutated tumor suppressor gene has been inherited.

Tumor Suppressor Genes, cont. • Examples of mutated tumor suppressor genes include: – BRCA-1 associated with breast cancer – APC associated with colon cancer – p 53 associated with over 50% of human cancers • The p 53 tumor suppressor gene is important for the coding of enzymes that are important in DNA repair, apoptosis, and regulation of cell division: – p 53 senses DNA damage and induces cell division arrest and DNA repair. – Unrepairable DNA is directed to apoptosis by the p 53 gene.

p 53 • p 53 is a guardian of the genome. • Its homozygous loss leads to accumulation of damaged DNA, which may lead to malignancy. – A mutation of the p 53 gene could result in a cell escaping apoptosis. – This becomes especially important for cells with unrepaired DNA because they may continue to divide. – If they continue to divide in an unregulated manner, the pool of mutated DNA in a tissue may be increased. – Further mutations of these types of cells can result in unregulated cell growth and division, the hallmark of cancer. • Some studies suggest that the mutated p 53 gene can be inherited, thus posing an additional risk factor for the development of cancer.

History of Chemical Carcinogenesis • The area of chemical carcinogenesis today is one of intense research that has led to a rich scientific literature on the relationship between chemical exposures and the development and mechanisms that underlie the process of carcinogenesis. • Early recognition of a relationship between chemicals and an increased incidence of cancer include the observations of: – John Hill, who in 1761 observed a causal relationship between nasal cancer in snuff users – Sir Percival Pott, who in 1775 recognized that soot and coal tar were the likely causal agents of scrotal cancer.

History of Chemical Carcinogenesis Early recognition of a relationship between cancer and genetics can be attributed to the following researchers: – Theodore Bovari – Furthand Kahn – James and Elizabeth Miller

History of Chemical Carcinogenesis • Researcher: – Theodore Bovari in 1914 hypothesized that alterations in the genetic material of the cells of the body are somehow involved in the process that produces cancer. This idea has been referred to as the somatic mutation theory.

History of Chemical Carcinogenesis • Researcher: – Furthand Kahn in 1934 experimentally used animal tumors to test cells for their ability to produce tumors in a tumor-free animal. It was observed that when the cells were introduced into a tumor-free host animal, similar tumors could be produced.

History of Chemical Carcinogenesis • Researchers: – James and Elizabeth Miller in the 1950 s recognized the relationship between metabolism and the bioactivation of carcinogens to produce metabolites that could bind to the macromolecules of the cell. The process of metabolism was recognized to produce electrophilic products, more reactive than the unmetabolized parent chemicals, thus establishing what has been referred to as the electrophilic theory of carcinogenesis.

Characteristics of Cancer Cells • The malignant phenotype refers to the structural, functional, and behavioral differences in the cells of malignant neoplasms, including: – Loss of contact growth inhibition – Autonomy of proliferation – Avoidance of apoptosis – Aberrant differentiation – Induction of angiogenesis

Tumor Angiogenesis, Metastasis, and Staging • A pathologist can assign the tumor a grade from 1 to 4 that corresponds to its degree of malignancy, with 4 being the most malignant and 1 being benign. • The more malignant the tumor, the less organized the cells of the tissue are and the more anaplastic or dedifferentiated they appear. • The prognosis worsens as cells become less differentiated, that is, a well-differentiated cancer carries a better prognosis than one that is poorly differentiated.

Malignant neoplasms are graded on the basis of differentiation

Benign Tumors • The tissues that make up the organs of our body may consist of numerous cell types. – Parenchymal cells are the functional cells that are recognized as being unique to that organ. • For example, in the liver we can recognize the parenchyma as consisting of the hepatocyte, which is the cell type that we associate with liver function. – Stromal cells, which are important to the tissue, may be viewed as supportive in nature. • The hepatocytes within the liver require connective tissue and blood vessels to support their function.

Benign Tumors, cont. • Similarly, a neoplasm consists of both parenchymal and stromal components. • In benign neoplasms the parenchymal and stromal cells may closely resemble those of the normal surrounding tissue.

Naming of Benign Neoplasms

Malignant Tumors • Malignant tumors are similarly named for the tissue from which the tumor is derived; one of three suffixes is generally attached to create the name of the cancer: – Carcinomas: epithelia tissue origin and the most common of all human malignancies (approximately 90%). This cancer spreads primarily through the lymphatic system. – Sarcomas: connective tissue origin. – Blastomas: derived from (or resembling) embryonic tissue

Naming of Malignant Tumors

Malignant Tumors • The malignant tumor grows within its tissue of origin; however, it may spread beyond these local confines. • Malignant tumor cells can invade into deeper layers of tissue (invasion) and are capable of metastasis as well. • Malignant tissue has requirements for adequate levels of oxygen, the removal of metabolic wastes, and a supply of nutrients and other factors.

Malignant Tumors, cont. • Tumors release a number of factors that collectively can be referred to as angiogenic factors. – Vascular endothelial growth factor is one such factor that stimulates the growth of capillaries into the tumor. – This is the process of angiogenesis, which serves a dual role in that it provides the vascular support for the tumor proper and provides close access of blood vessels for metastasis. • Another management approach in treating patients with cancer is to use drugs such as endostatin that inhibit the angiogenesis process.

Metastasis • Cancer cells can breach the basement membrane and produce chemicals that can break down the membrane, thus facilitating their entry into the deeper tissue. • Malignant cells that gain entry into the lymphatic and blood vessels can travel within the circulation until such time as they receive appropriate signals to attach to the vessel wall and move into new tissue. • This process is referred to as metastasis, and it results in a secondary tumor.

Carcinogen Classification • Based on Chemistry – Thousands of suspected carcinogens have already been tested for their ability to produce mutations and cancer in laboratory animals and in vitro systems. – These chemicals fall into many different categories of chemical agents based on shared structural similarities.

Carcinogen Classification • Based on Mechanism of Action – Genotoxic • Carcinogens can be classified by their mode of action, genotoxic or nongenotoxic. Genotoxic carcinogens are DNA reactive or DNA-reactive metabolites capable of altering the integrity DNA through direct interaction. – Nongenotoxic • Nongenotoxic carcinogens do not directly cause DNA mutation. The mechanism of action is • poorly understood.

Carcinogen Classification • Genomic information can be classified as genetic or epigenetic. The genetic information is the sequence of bases encoding the proteins, and epigenetic information is the regulation of gene expression by means other than alterations in the DNA sequence. • DNA methylation is also involved in DNA repair, regulation of chromatin structure, and genome instability. • Epigenetic carcinogens can be defined as solid state, hormonal, immunosuppressant, cocarcinogenic, or promoter. • The evidence for epigenetic mechanisms for some chemicals includes the following observations: – Not all carcinogens are mutagens. – Carcinogenesis is often associated with changes in the methylation of DNA.

Exposure to Carcinogens • The U. S. governmental regulatory definition of a carcinogen is “any substance at any dose, administered by any route, that increases tumor incidence in rats. ” • The word tumor, as used in the regulatory definition, is not synonymous with cancer because we know that tumors can be either benign or malignant.

Chemical-Induced Carcinogenesis Is a Multistep Process • Initiation - the genotoxic event that leads to mutations of the DNA and places the affected cells at a greater risk for tumor formation. • Promotion - the second step in the carcinogenesis process, which moves initiated cells further along their transformation process. Exposure of initiated cells to chemicals that stimulate cell proliferation, such as irritating substances, results in the production of a clone of proliferating cells within the tissue. • Progression - Progression is the next step toward the transformation of cells into a tumor that is malignant. At this stage in the process, and depending on the particular tissue of origin of the cell, a high growth rate and invasion into surrounding tissue may occur.

Cancer is a Multistep Process

Informing the Public on Carcinogens • The federal government has the obligation to inform the public about known and anticipated human carcinogens. • The Report on Carcinogens is a document prepared in response to section 301 of the U. S. Public Health Service Act. • It is stipulated that the Secretary of the Department of Health and Human Services shall publish a report that contains a list of all substances: – That either are known to be human carcinogens or may reasonably be anticipated to be human carcinogens – To which a significant number of persons residing in the United States are exposed • The responsibility for the preparation of this document has been delegated to the NTP.