Chapter 22: Abnormal Cell Growth

Intro

Contents

OVERVIEW

Cells are often lost through death (apoptosis and necrosis), sloughing (e.g., shedding of cells lining the gastrointestinal tract and skin), or injury (e.g., bleeding). New cells replace cells at the same rate they are lost, a highly regulated state of balance known as homeostasis. If normal cellular regulatory mechanisms malfunction, unregulated and unchecked cell division may result, a condition known as cancer.

Protooncogenes regulate or produce proteins that regulate normal cell growth and development. Mutations that alter protooncogenes may convert them from regulatory genes into cancer-causing oncogenes. In addition, mutations that create a loss of function in genes known as tumor suppressor genes may also induce cancer.

Most genetic changes that occur during carcinogenesis (transformation of normal cells to cancer cells) are somatic mutations. Each time a cell divides, there is a chance of somatic mutation; therefore, there is always a low background risk for cancer. A far more prevalent cause of cancer is environmental exposure.

GENES AND CANCER

The regulation of cell cycle progression is controlled by protooncogenes, which promote cell cycle progression, and tumor suppressor genes, which function to control the rapid progression through the cell cycle.

Protooncogenes and oncogenes

Cell division is controlled by a number of cellular proteins. Because these proteins are the products of genes, genetic mutation may result in deregulated cellular proliferation. Protooncogenes are genes whose protein products control cell growth and differentiation. These genes undergo mutations causing qualitative and quantitative changes in gene products and are then called oncogenes. Our knowledge of protooncogenes stems from molecular genetic studies on the defective gene product.

1.  Protooncogenes: Protooncogenes stimulate the cell cycle and have been identified at all levels of the various signal transduction cascades that control cell growth, proliferation, and differentiation. As normal regulatory elements, protooncogenes function in a wide variety of cellular pathways (Figure 22.1). Mutations can occur in any of the steps involved in regulating cell growth and differentiation. When such mutations accumulate within a particular cell type, the progressive deregulation of growth eventually produces a cell whose progeny forms a tumor.

  FIGURE 22.1.Protooncogenes and their roles in regulating growth.

Protooncogenes and their roles in regulating growth.

2.  Several ways of activating protooncogenes to oncogenes: Point mutations, insertion mutations, gene amplification, chromosomal translocation (Chapter 8), and/or changes in expression of the oncoprotein can all result in deregulated activity of these genes (Figure 22.2).

FIGURE 22.2.Mechanism of conversion of protooncogenes to oncogenes.

Mechanism of conversion of protooncogenes to oncogenes.

Tumor suppressor genes

Tumor suppressor genes are important for maintaining normal cell growth control by curtailing unregulated progression through the cell cycle. Situations that diminish tumor suppressor gene function may lead to neoplastic changes.

1.  Loss of function: Loss of tumor suppressor genes predisposes cells to cancer. Protein products of protooncogenes are involved in growth stimulation; the protein products of tumor suppressor genes repress cell growth and division. Therefore, loss of gene function (through mutations and other alterations) can lead to cell transformation by removing the restraints that normally regulate cell growth.

2.  p53—guardian of the genome: The most frequently inactivated tumor suppressor gene is the p53 gene, which encodes a protein with a 53 kilodalton molecular mass, or p53, which is most often implicated in cancer development. More than half of human cancers show p53 mutations (Chapter 21). Loss of p53 function can contribute to genomic instability within cells (Figure 22.3). p53 is important in preventing cancer because of its unique functional capabilities.

  FIGURE 22.3. p53—guarding the genome.

p53—guarding the genome.

p53

  • regulates gene expression and controls several key genes involved in growth regulation.
  •  facilitates DNA repair. When DNA damage is encountered, p53 senses the damage and causes G1 arrest of the cells, until the damage is repaired.
  •  activates apoptosis of damaged cells. When damage to DNA within cells is beyond repair, p53 functions to trigger apoptosis in these cells.

Retinoblastoma

Retinoblastoma is an embryonic malignant neoplasm of retinal origin that occurs in germ line (40%) and sporadic (60%) forms. Germ line disease includes those patients with a family history (hereditary disease) and those patients who have sustained a new germ line mutation at the time of conception. The genetic locus responsible for a predisposition to retinoblastoma is located within the q14 band of chromosome 13. The retinoblastoma gene, RB, was cloned in 1987 and was the first tumor suppressor gene cloned. Patients with the germ line type of retinoblastoma have a markedly increased frequency of second malignant tumors—the most common being osteosarcomas.


Dominant and recessive nature of oncogenes and tumor suppressor genes

Some genetic mutations confer a growth advantage to the cell that contains it, allowing selective growth of these cells. Therefore, when protooncogenes undergo mutations, they are “activated” to oncogenes (Figure 22.4). Because these genes normally regulate growth, mutations in them often favor the unregulated growth of cancer. Generally, tumor suppressor genes are “inactivated” by mutations and deletions, resulting in the loss of function of the protein and in unregulated cell growth. Both copies of the tumor suppressor genes have to be mutated or lost for loss of growth control; therefore, these genes act recessively at cell level. Oncogenes, on the other hand, are dominant in action requiring mutation of only one copy of a protooncogene (Figure 22.4).

FIGURE 22.4. Oncogenes are dominant in action at the cell level and tumor suppressor genes are recessive.

Oncogenes are dominant in action at the cell level and tumor suppressor genes are recessive.


MicroRNAs as oncogenes and tumor suppressors

As a class, microRNAs (miRNAs) regulate gene expression by controlling the levels of target RNA posttranscriptionally. They are encoded within the noncoding and intron regions of different genes and are transcribed into RNA, but not protein. These single-stranded RNA molecules are approximately 21 to 23 nucleotides in length and are processed from primary transcripts known as pri-miRNA into short stem-loop structures, pre-miRNA, and finally to functional miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules and function to downregulate gene expression.

miRNAs are thought to affect the expression of critical proteins within the cell, such as cytokines, growth factors, transcription factors, etc. The expression profiles of miRNAs are frequently altered in tumors. When miRNA’s targets are oncogenes, their loss of function results in increased target gene expression. Conversely, overexpression of certain miRNAs may decrease the levels of protein products of target tumor suppressor genes. Therefore, miRNAs behave as oncogenes and tumor suppressor genes. New insights into miRNAs function may also advance the diagnosis and treatment of cancer.


MOLECULAR BASIS OF CANCER

Cancer is a stepwise process. Often, several genetic alterations must occur at specific sites before malignant transformation is seen in most adult cancers. Cancers of childhood appear to require fewer mutations before manifestation of overt cancer. Rare inherited mutations can predispose individuals to cancer at one or more sites. This type of mutation is present virtually in all somatic cells of the body.

Growth regulation

Normal cells respond to a complex set of biochemical signals, which allow them to develop, grow, differentiate, or die. Cancer results when any cell is freed from these types of restrictions and the resultant abnormal progeny of cells are allowed to proliferate.

Cancer genesis—a multistep process

Mutations in the key genes have to accumulate over time to create a progeny of cells that have lost most control over growth. Each individual mutation contributes in some way to eventually producing the malignant state. The accumulation of these mutations spans several years and explains why cancers take a long time to develop in humans (Figure 22.5). Both exogenous (environmental insults) and endogenous processes (carcinogenic products generated by cellular reactions) may damage DNA. DNA damage that goes unrepaired may lead to mutations during mitosis. Increased errors during DNA replication or a decreased efficiency of DNA repair may favor increased frequency of genetic mutations. Cells become cancerous when mutations occur in protooncogenes and tumor suppressor genes.

FIGURE 22.5.Colon cancer progression.

Colon cancer progression.

Theories of cancer

It has been long known that cancer cells are genetically unstable. Only in the last two decades has it been realized that specific genes are responsible for this instability. Nearly 200 oncogenes and 170 tumor suppressor genes have been identified. Additional genes that aid in breaking down basement membranes of cells and allow for their movement are also known to be important in oncogenesis. Despite the large number of possible genetic permutations, certain combinations of these mutant genes were found in distinct cancers and also different types of cancer from the same tissue. From these observed patterns came several distinct theories of cancer formation.

1.  Clonal evolution model: This model was proposed in the 1970s to explain how cancers evolve. According to this model, initial damage (a genetic mutation) occurs in a single cell, giving it a selective growth advantage and time to outnumber neighboring cells. Within this clonal population, a single cell may acquire a second mutation, providing an additional growth advantage and allowing it to expand and become the predominant cell type. Repeated cycles followed by clonal expansion eventually lead to a fully developed malignant tumor. Accumulated mutations within key genes trigger a single transformed cell to eventually develop into a malignant tumor (Figure 22.6).

FIGURE 22.6.Theory of clonal evolution.

Theory of clonal evolution.


Angiogenesis and tumor progression

As cancers progress, they accumulate in mass. To obtain the necessary nutrition and oxygen for their continued growth and survival, it is critical for tumors to have adequate blood supply. Cancer cells create new blood supply to sustain their growth by several mechanisms. Angiogenesis, or neovascularization, can be both activated and inhibited. Under normal physiologic conditions, angiogenic inhibitors predominate, blocking the growth of new blood vessels. When there is a need for new vasculature, activators increase in number and inhibitors decrease.

Tumors release two proangiogenic factors, which are important for sustaining tumor growth: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Several angiogenesis inhibitors and antibodies to proangiogenic growth factors are currently in clinical trials to inhibit tumor progression. One mechanism for tumor neovascularization involves mutation of p53 gene. Typically, wild type p53 regulates the expression of an angiogenesis inhibitor, thrombospondin. Mutations in p53 facilitate neovascularization due to the lack of production of thrombospondin.


2. Hallmarks of cancer: The number of genes identified in cancers is constantly growing and the complexity of these observations has been recently streamlined into a series of genetic and cellular principles that may govern the formation of most, if not all, types of human cancers (Figure 22.7). According to this theory, oncogenesis requires cells to

FIGURE 22.7.Hallmarks of cancer.

Hallmarks of cancer.

  • acquire self-sufficiency of growth signals
  • become insensitive to growth inhibitory signals
  • evade apoptosis
  • acquire limitless replicative potential, and
  •  sustain angiogenesis

According to this model, the type of genetic insult may vary with different cancers. All cancers, however, should acquire damage to these different classes of genes until a cell loses a critical number of growth control mechanisms and initiates a tumor.

3. Stem cell theory of cancer: This theory accounts for the observations that tumors contain cancer stem cells with indefinite proliferative potential similar to adult stem cells. Because hematopoietic stem cell lineages have been well characterized, most of our evidence for cancer stem cells has come from leukemias. Cancer stem cells are thought to be self-renewing and responsible for all components of a heterogeneous tumor. These tumor-initiating cells tend to be drug resistant and to express markers typical of stem cells. The cancer stem cell model is also consistent with some clinical observations, in which standard chemotherapy has not been successful in destroying all tumor cells and some cells remain viable. Despite the small number of cancer stem cells, according to this theory, they may be responsible for tumor recurrence years after “successful” treatment (Figure 22.8). Several genes have been identified that can confer self-renewal properties to committed progenitors and mediate their neoplastic transformation.

FIGURE 22.8.Stem cell theory of cancer.

Stem cell theory of cancer.

Tumor progression

Cancer cells gain metastatic abilities as they evolve. Among these are genes whose products allow the breakdown of tissue structure and invade the basement membrane, allowing cells to migrate to other sites. In addition, as tumors accumulate in cellular mass, it is critical that they induce the growth of blood vessels, or angiogenesis, to supply the growing tumor with adequate nutrition and oxygen for its continued growth and survival.

INHERITED MUTATIONS OF CANCER GENES

Even though the number of individuals with inherited predisposition is low when compared to the total number of human cancers, the risk for cancer is severalfold higher in the individual carrying a mutation in the cancer-causing gene, as this is inherited through the germ line and is therefore present in every cell of the body.

Inherited mutations mostly affect tumor suppressor genes

A large percentage of genes that are mutated in familial cancers are due to tumor suppressor genes. Some examples are shown in Table 22.1. Mutation in protooncogenes during development may not be compatible with life. This highlights the importance of orderly growth during embryogenesis to produce a viable fetus, which is better facilitated with the loss of a copy of a tumor suppressor gene than in the presence of an oncogene.

TABLE 22.1.Examples of Familial Cancer Syndromes

Syndrome Primary Tumor Associated Conditions Gene Function of Gene Product
Familial breast cancer Breast cancer Ovarian cancer BRCA1 Repair of double strand DNA breaks
Breast cancer Ovarian cancer
Pancreatic cancer
Melanoma
BRCA2 Repair of double strand DNA breaks
Li-Fraumeni Sarcomas
Breast cancer
Leukemias
Brain tumors
P53 Transcription factor
Apoptosis Cell cycle arrest
Hereditary nonpolyposis colon cancer Colorectal cancer Endometrial
Ovarian
Bladder
Glioblastoma
MSH2
MLH1
Repair of DNA mismatches
Maintains DNA stability
Familial adenomatous polyposis Colorectal cancer Duodenal
Gastric tumors
APC Regulation of ? catenin levels
Cell adhesion
Familial retinoblastoma Retinoblastoma Osteosarcoma RB Cell cycle regulator
Transcription factor

Inherited mutations and cancer risk

Cancer risk in those individuals carrying a mutation in a cancer-causing gene is severalfold greater, because the presence of the mutation in every cell in their bodies makes it highly likely for other mutations to occur.

MUTATIONS IN DRUG-METABOLIZING ENZYMES AND CANCER SUSCEPTIBILITY

Environmental chemicals may be classified as either genotoxic or nongenotoxic. Genotoxic chemicals interact with DNA, causing mutations in critical genes. Nongenotoxic mechanisms differ depending upon the nature of the chemical compound. Chemical carcinogenesis is a multistep process (Figure 22.9). Chemicals that have no appreciable carcinogenic potential of their own but greatly enhance tumor development when exposed to them for long periods of time mediate tumor promotion. In terms of lifestyle, exogenous hormones, high-fat diet, alcohol, etc. are known to promote cancer and therefore can be an important determinant of cancer risk.

FIGURE 22.9.Chemical carcinogenesis.

Chemical carcinogenesis.


Mutations in P53 mirror etiological agent in human carcinogenesis

The p53 tumor suppressor gene is mutated in over 50% of lung, breast, colon, and other common tumors; the mutational spectrum varies by cancer type and environmental exposure, providing clues to the specific risk factors involved.

Mutations in the specific codon of the p53 gene occur in lung, head, and neck cancers when benzopyrene adducts (cigarette smoke, environmental carcinogens) bind to DNA. In geographic areas in which aflatoxins and hepatitis B are risk factors for liver tumors, specific p53 mutations (codon 249, AGG to AGT) are seen to occur in these tumors.

Alterations seen in the P53 gene in squamous and basal cell carcinomas of skin are hallmarks of exposure to ultraviolet light. Cervical tumors are due to human papillomavirus (HPV) infection. In HPV-positive tumors, p53 remains wild type, but binding to HPV causes its rapid degradation. p53 is an example of how several of the capabilities of cancer are realized with its loss and underscores its importance in the prevention of cancer.


While genetic predisposition, ethnicity, age, gender, and, to some extent, health and nutritional impairment are cancer susceptibility factors, recent studies are showing polymorphisms in certain drug-metabolizing enzymes to be associated with this inter-individual variation (Figure 22.10). Variations in the expression or form of the drug-metabolizing genes, such as cytochrome P450, glutathione transferase, and N-acetyl transferase genes, strongly influence individual biologic response to carcinogens.

FIGURE 22.10.Drug-metabolizing enzymes and cancer risk.

Drug-metabolizing enzymes and cancer risk.

While inheritance of cancer-causing genes will increase the cancer risk, its occurrence in the population is low. On the other hand, the carcinogen-metabolizing enzymes exist in different forms within the population at a high rate and will increase the cancer risk in some individuals carrying the form that allows activation of certain carcinogens.

Chapter Summary

  • Cancer is a multistep process.
  •  There are several characteristic features that a cell has to attain before it undergoes neoplastic transformation.
  •  Protooncogenes are normal counterparts of oncogenes and usually have a role in growth regulation.
  •  Tumor suppressor genes normally restrain growth.
  •  Protooncogenes undergo mutations that cause them to be overactive or function without regulation.
  •  Tumor suppressor genes lose function when mutated.
  •  Oncogenes are dominant in action and tumor suppressor genes are recessive.
  •  Mutation in DNA repair genes can cause cancer.
  •  Inherited predisposition to cancer accounts for 5% to 10% of all human cancers.
  •  Lifestyle factors influence cancer risk in the general population.
  •  Polymorphism in drug-metabolizing enzymes explains cancer susceptibility in the general population.
  •  Germ line mutations in cancer-causing genes occur infrequently.
  •  Polymorphism in drug-metabolizing enzymes occurs more frequently.
  •  Mutations in p53 gene are the most common cancer-associated mutations and its function underscores its importance in the prevention of cancer.