Molecular Basis of Cancer



General Pathology

Dr.Ban AL Drobie

The Molecular Basis of Cancer

Cancer is a multi-step process, therefore multiple genetic events (mutations) will occur in tumors

Fundamental Principles

Some fundamental principles before delving into the details of the molecular basis of cancer:

1- Nonlethal genetic damage (mutation)

Nonlethal genetic damage lies at the heart of carcinogenesis. This may be acquired through environmental agents (chemicals, radiation, or viruses),

or inherited in the germ line.

The genetic hypothesis of cancer states that a tumor mass results from the clonal expansion of a single progenitor cell that has sustained genetic damage (i.e., tumors are monoclonal).

2- “Targets of genetic damage”:

1. growth-promoting proto-oncogenes

2. growth-inhibiting tumor suppressor genes

3. Apoptosis-regulating genes

4. DNA repair genes

Collectively the genetic alterations in tumor cells provide them growth and survival advantages over normal cells.

1-Protooncogenes: are the normal cellular counterparts of oncogenes. They are physiologic regulators of cell proliferation and differentiation.

Oncogenes: They are the mutant alleles of proto-oncogenes, these are dominant because mutation of a single allele can lead to neoplastic transformation. They promote autonomous cell growth in cancer; oncogenes are characterized by the ability to promote cell growth in the absence of normal mitogenic signals.

The products of oncogenes are called oncoproteins, they resemble the normal products of protooncogenes with the exception that oncoproteins are devoid of important regulatory elements. Their production in the transformed cells is not dependent on growth factors or other external signals.

2-Tumor suppressor genes: are genes that normally prevent uncontrolled growth and, where mutation of the gene leads to transformation by unleashing the brakes on cellular proliferation. P53 and Retinoblastoma genes (RB) are examples of tumor suppressor genes. Both normal alleles must be damaged for transformation to occur (recessive oncogenes).

3-Genes that regulate apoptosis: may be dominant, or recessive. act by enhancing cell survival, rather than stimulating proliferation .Genes of this class that protect against apoptosis are often overexpressed in cancer cells, whereas those that promote apoptosis tend to be underexpressed or functionally inactivated by mutations.

4- DNA repair genes: Those genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes,. A disability in the DNA repair genes can predispose to mutations in the genome and hence to neoplastic transformation.

TUMOR PROGRESSION

Fortunately, in most if not all instances, no single mutation is sufficient to transform a normal cell into a cancer cell.

Carcinogenesis is a multistep process resulting from the accumulation of multiple mutations. Over a period of time, many tumors become more aggressive by acquiring greater malignant potential. This phenomenon is referred to as tumor progression. Increasing malignancy is often acquired step by step. At the molecular level, tumor progression result from multiple mutations that accumulate independently in different cells, generating subclones with different characteristics such as ability to invade, rate of growth, metastatic ability, hormonal responsiveness, and susceptibility to anti-neoplastic drugs. Even though most malignant tumors are monoclonal in origin, by the time they become clinically evident; their constituent cells are extremely heterogeneous.

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Fig. 6.16  Development of cancer through stepwise accumulation of complementary driver mutations. The order in which various driver mutations occur is usually unknown and may vary from tumor to tumor. 

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A simplified scheme of the molecular basis of cancer

HALLMARKS OF CANCER

The following are fundamental changes in cell physiology that together determine malignant phenotype.

1-Self-sufficiency in growth signals: Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation.

2-Insensitivity to growth-inhibitory signals: Tumors may not respond to molecules that are inhibitory to the proliferation of normal cells.

3-Evasion of apoptosis: Tumors may be resistant to programmed cell death, as a consequence of inactivation of p53 or other changes.

4-Altered cellular metabolism:

5-Limitless replicative potential: Tumor cells have unrestricted proliferative capacity, associated with maintenance of telomere length and function.

6-Sustained angiogenesis: Tumors are not able to grow without formation of a vascular supply, which is induced by various factors, the most important being vascular endothelial growth factor (VEGF).

7- Ability to invade and metastasize: Tumor metastases are the cause of the vast majority of cancer deaths.

8-Another important change for tumor development is the escape from immunity

1-SELF-SUFFICIENCY IN GROWTH SIGNALS:

Physiologic cell proliferation includes:

|  |•    |The binding of a growth factor to its specific receptor generally located on the cell membrane |

|  |•    |Transient and limited activation of the growth factor receptor, which, in turn, activates several proteins on the inner side of the |

| | |plasma membrane |

|  |•    |Transmission of the signal across the cytosol to the nucleus via second messengers that directly activate transcription |

|  |•    |Induction and activation of nuclear regulatory factors that initiate DNA transcription |

|  |•  |Entry and progression of the cell into the cell cycle, ultimately resulting in cell division |

| |  |[pic] |

| | |Model for action of RAS genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) RAS is activated|

| | |to a GTP-bound state |

| | | |

| | |ONCOPROTEINS |

| | |These are the protein products of oncogenes. They include: |

| | | |

| | |1- Growth factors: All normal cells require stimulation by growth factors to undergo proliferation. Most soluble growth factors are |

| | |made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action). In contrast, many cancer cells |

| | |acquire growth self-sufficiency by synthesizing the same growth factors to which they are responsive (autocrine action). Many sarcomas |

| | |make both transforming growth factor-α (TGF-α) and its receptor |

| | | |

| | |2- Growth factor receptors: |

| | |Mutant genes lead to one of two consequences |

| | |a. Formation of mutant receptor proteins that deliver continuous mitogenic signals to cells, even in the absence of the relevant growth|

| | |factor in the environment. |

| | |b. Overexpression of growth factor receptors that render cancer cells hyper-responsive to levels of the growth factor that would not |

| | |normally trigger proliferation. ex. Overexpression of the epidermal growth factor (EGF) receptor in 80% of squamous cell carcinomas of |

| | |the lung. |

| | |HER2/NEU receptor is amplified in 25% to 30% of breast cancers. High level of HER2/NEU protein in breast cancer cells is associated |

| | |with poor prognosis |

| | | |

| | |3- Signal transducing proteins: most of these are located in the inner leaflet of the plasma membrane where they receive signals from |

| | |outside the cell & transmit them to the nucleus. |

| | |RAS is a commonly mutated proto-oncogene in human tumors (30% of all human neoplasms contain mutated RAS gene. Activated RAS stimulates|

| | |down-stream regulators of proliferation, which floods the nucleus with signals for cell proliferation. |

| | | |

| | |4- Nuclear transcription proteins: DNA replication & cell division are regulated by genes whose products are localized to the nucleus |

| | |where they control the transcription of growth related genes. e.g. c-myc. |

| | |MYC oncogenes: oncoproteins of the MYC oncogene are transcription factors regulating the expression of growth-promoting cyclins. In |

| | |normal cells, MYC levels decline to basal level when the cell cycle begins. In contrast, oncogenic versions of the MYC gene are |

| | |associated with persistent expression or overexpression, contributing to sustained proliferation. Dysregulation of the MYC gene |

| | |resulting from a t(8;14) translocation occurs in Burkitt lymphoma. |

| | | |

| | |5- Cyclins and Cyclin-Dependent Kinases (CDKs) |

| | |The orderly progression of cells through the various phases of the cell cycle is orchestrated by CDKs. They are activated by binding to|

| | |cyclins. On completion of their role, cyclin levels decline rapidly. (Mutations that dysregulate the activity of cyclins and CDKs would|

| | |favor cell proliferation. |

2-INSENSITIVITY TO GROWTH INHIBITORY SIGNALS: TUMOR SUPPRESSOR GENES

CANCER SUPPRESSOR GENES

Whereas oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes apply brakes to cell proliferation.

Malignancy occurs when the cell becomes homozygous for the mutant allele .

1.Retinoblastoma gene (RB) Governor of the Cell Cycle

(RB) gene is the first and prototypic cancer suppressor gene to be discovered. The discovery of cancer suppressor genes was accomplished by the study of retinoblastoma, an uncommon childhood tumor of the eye.

Although the loss of normal RB genes was discovered initially in retinoblastomas, it is now evident that homozygous loss of this gene (i.e., loss of both alleles) is a fairly common event in several cancers, such as that of the breast, lung, and bladder

2.The p53 gene (guardian of the genome)

The p53 tumor suppressor gene is one of the most commonly mutated genes in human cancers..Normal p53 prevents neoplastic transformation by three interlocking mechanisms:

1. Activation of temporary cell cycle arrest (cell quiescence)

2. Induction of permanent cell cycle arrest (cell senescence)

3. Triggering of programmed cell death (apoptosis).

p53 senses DNA damage and assists in DNA repair by causing G1 arrest and inducing DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to either enter senescence or undergo apoptosis. In view of these activities, p53 has been called a "guardian of the genome." With homozygous loss of p53, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a one-way street leading to malignant transformation. More than 70% of human cancers have a defect in p53

3. Transforming Growth Factor-β (TGF- β) Pathway

TGF-β is a potent inhibitor of proliferation. In many forms of cancer, the growth-inhibiting effects of TGF-β pathways are impaired by mutations in the TGF-β signaling pathway

3-EVASION OF APOPTOSIS

The accumulation of neoplastic cells may occur not only by the activation of oncogenes or inactivation of tumor suppressor genes, but also by mutations in the genes that regulate apoptosis. A large family of genes that regulate apoptosis has been identified in both normal and cancer cells. P53 gene is also involved in apoptosis.

Overexpression of the BCL2 protein (anti-apoptotic protein) protects tumor cells from apoptosis. About 85% of follicular lymphoma ,carry a characteristic t(14;18) translocation. At chromosome 14 break occurs at the site where immunoglobulin heavy-chain genes are found ,Juxtaposition of this transcriptional active locus with BCL2 (located at 18) causes overexpression of the BCL2 protein. This in turn protects lymphocytes from apoptosis and allowing them to survive for long periods. There is therefore a steady accumulation of B lymphocytes, resulting in lymphadenopathy and marrow infiltration.

The role of p53 in maintaining the integrity of the genome

4-ALTERED CELLULAR METABOLISM

Cancer cells demonstrate a distinctive form of cellular metabolism characterized by high levels of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway. This phenomenon, called the

Warburg effect and also known as aerobic glycolysis. Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular component

5-LIMITLESS REPLICATIVE POTENTIAL: TELOMERASE

After a fixed number of divisions, normal cells become arrested in a terminally nondividing state known as replicative senescence. It has been noted that with each cell division there is some shortening of specialized structures, called telomeres, at the ends of chromosomes. Once the telomeres are shortened beyond a certain point,

the loss of telomere function leads to activation of p53-dependent cell-cycle checkpoints, causing proliferative arrest or apoptosis. Thus, telomere shortening functions as a clock that counts cell divisions.

Tumor cells also must develop ways to avoid cellular senescence which is acquired by the activation of the telomerase enzyme that can maintain normal telomere length and thus continue to divide. Telomerase is active in normal stem cells, which explain the ability of these cells to self-replicate extensively. This enzyme is absent from most somatic cells, and hence they suffer progressive loss of telomeres and stop to divide eventually.

6-DEVELOPMENT OF SUSTAINED ANGIOGENESIS

Tumors stimulate the growth of host blood vessels, a process called angiogenesis (the formation of new vessels from pre-existing ones), which is essential for supplying nutrients to the tumor. Even with genetic abnormalities that dysregulate growth and survival of individual cells, tumors cannot enlarge beyond 1 to 2 mm in diameter or thickness unless they are vascularized. Presumably the 1- to 2-mm zone represents the maximal distance across which oxygen and nutrients can diffuse from blood vessels. Beyond this size, the tumor fails to enlarge without vascularization because of hypoxia-induced cell death by P53 activation. Angiogenesis is a requisite not only for continued tumor growth, but also for metastasis. Without access to the vasculature, the tumor cells cannot readily spread to distant sites.

7-INVASION AND METASTASIS

The spread of tumors is a complex process involving a series of sequential steps.

A cancer first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane. This cycle is repeated when tumor cell emboli extravasate at a distant site.

Invasion of Extracellular Matrix (ECM)

Invasion of the ECM is an active process that requires four steps:

1-Detachment of tumor cells from each other

2-Degradation of ECM

3-Attachment to new ECM components

4- Migration of tumor cells

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Sequence  of  events  in  the  invasion  of  epithelial  basement  membranes by  tumor  cells.  Tumor  cells  detach  from  each  other  because  of  reduced  adhesiveness  and  attract  inflammatory  cells.  Proteases  secreted from tumor cells and inflammatory cells degrade the basement membrane. Binding of tumor cells to proteolytically generated binding sites and tumor cell migration follow

.

Vascular Dissemination and Homing of Tumor Cells

When in the circulation, tumor cells are vulnerable to destruction by host immune cells. In the bloodstream, some tumor cells form emboli by aggregating and adhering to circulating leukocytes & platelets. Extravasation of free tumor cells or tumor emboli involves adhesion to the vascular endothelium, followed by passing through the basement membrane into the organ parenchyma by mechanisms similar to those involved in invasion.

The site of extravasation and the organ distribution of metastases generally can be predicted by the location of the primary tumor and its vascular or lymphatic drainage. However, in many cases the natural pathways of drainage do not readily explain the distribution of metastases..

GENOMIC INSTABILITY DUE TO DEFECTS IN DNA REPAIR

Mutations are at the heart of carcinogenesis. Although humans literally swim in environmental agents that are mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively rare outcomes of these encounters. This results from the ability of normal cells to repair DNA damage. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Individuals born with such inherited defects in DNA repair proteins are at a greatly increased risk of developing cancer.

Hereditary Nonpolyposis Colon Cancer Syndrome (HNPCC)

This disorder is characterized by familial carcinomas of the colon that affect predominantly the cecum and proximal colon. It results from defects in genes involved in DNA repair. Without these repair genes, errors gradually accumulate in several genes, including proto-oncogenes and cancer suppressor genes.

XerodermaPigmentosum

Patients with this inherited disorder are at increased risk for the development of cancers of the skin exposed to the sun (UV) light. The basis of this disorder is defective DNA repair.

Diseases with Defects in DNA Repair by Homologous Recombination

Mutations in two genes, BRCA1 and BRCA2, account for 80% of cases of familial breast cancer. In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk of epithelial ovarian cancers. Likewise, mutations in the BRCA2 gene increase the risk of breast cancer in both men and women.. Similar to other tumor suppressor genes, both copies of BRCA1 and BRCA2 must be inactivated for cancer to develop.

ETIOLOGY OF CANCER: CARCINOGENIC AGENTS

Genetic damage lies at the heart of carcinogenesis. Three classes of gene damaging or carcinogenic agents can be identified:

Chemicals

Radiant energy

Microbial agents.

Chemicals and radiant energy are documented causes of cancer in humans, and oncogenic viruses are involved in at least some human tumors.

CHEMICAL CARCINOGENS

Direct-Acting Carcinogens

These require no metabolic conversion to become carcinogenic. They are in general weak carcinogens but are important because some of them are cancer chemotherapeutic drugs (e.g., alkylating agents)

Indirect-Acting Agents

This designation refers to chemicals that require metabolic conversion to an ultimate carcinogen. Examples include

1. The polycyclic hydrocarbons e.g. benzopyrene and other carcinogens are some of the most potent indirect chemical carcinogens. They are formed in the high-temperature combustion of tobacco in cigarette smoking. These products are implicated in the causation of lung cancer in cigarette smokers. Polycyclic hydrocarbons may also be produced from animal fats during the process of broiling meats. The principal active products in many hydrocarbons are epoxides, which form combine with molecules in the cell, principally DNA, but also with RNA and proteins.

2. The aromatic amines and azo dyes are another class of indirect-acting carcinogens. β-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye and rubber industries. Because indirect-acting carcinogens require metabolic activation for their conversion to DNA-damaging agents, much interest is focused on the enzymatic pathways that are involved, such as the cytochrome P-450-dependent monooxygenases.

3. Aflatoxin B1 is of interest because it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. There is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East.

4. Vinyl chloride, arsenic, nickel, chromium, & insecticides are potential carcinogens in the workplace and about the house.

5. Nitrites used as food preservatives have caused concern, since they cause nitrosylation of amines contained in the food. The nitrosoamines so formed are suspected to be carcinogenic

Mechanisms of Action of Chemical Carcinogens

Most chemical carcinogens are mutagenic; contain highly reactive electrophile groups that combine DNA (as well as proteins and RNA). Oncogenes and tumor suppressors (such as RAS and p53), are important targets of chemical carcinogens.

After exposure of a cell to a mutagen or an initiator, tumorigensis can be enhanced by subsequent administration of promoters (e.g., hormones, phenols, and drugs) that by themselves are nontumorigenic (not mutagenic) but induce cell proliferation.

tumor promoters act by stimulating cell proliferation..increased proliferation may occur through direct effects of tumors-promoter on target cells or may be secondary to tissue injury and regenerative repair

RADIATION CARCINOGENESIS

Radiation, whatever its source (UV rays of sunlight, x-rays, nuclear fission, radionuclides) is an established carcinogen. Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers. Follow-up of survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia- after an average latent period of about 7 years.Therapeutic irradiation of the head and neck can give rise to papillary thyroid cancers years later.

VIRAL AND MICROBIAL ONCOGENESIS

Only a few viruses have been linked with human cancer.

Oncogenic RNA Viruses

Human T-cell leukemia virus-1 (HTLV-1) is the only retrovirus that has been demonstrated to cause cancer in humans. HTLV-1 is associated with a form of T-cell leukemia/lymphoma that is endemic in certain parts of Japan and the Caribbean but is found sporadically elsewhere. Similar to the human immunodeficiency virus (HIV), HTLV-1 has tropism for CD4+ T cells, and this subset of T cells is the major target for neoplastic transformation

Oncogenic DNA Viruses

Human Papilloma virus

HPVs are associated with the following

1. Benign squamous papillomas (warts); these are caused by some types (e.g., HPV1, 2, 4, and 7).

2. Squamous cell carcinoma of the cervix and anogenital region; these are caused by high-risk HPVs (e.g., HPV 16 and 18).

3. Oropharyngealcanrcinomas: at least 20% of these are associated with HPV.

4. Genital warts (having low malignant potential); these are associated with low-risk HPVs predominantly HPV-6 and HPV-11.

The oncogenic potential of HPV can be related to products of two early viral genes, E6 and E7.

Infection with HPV itself is not sufficient for carcinogenesis. Association with a mutated RAS gene results in full malignant transformation. These data strongly suggest that HPV acts in concert with other environmental factors..

Epstein-Barr Virus (EBV)

This virus has been implicated in the pathogenesis of several human tumors:

Burkitt lymphoma

B-cell lymphomas in patients with immunosuppression including AIDS

A subset of Hodgkin lymphoma

A subset of nasopharyngeal carcinoma.

Hepatitis B and Hepatitis C Viruses

It is estimated that 80% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV..

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Helicobacter pylori

H. pylori is the first bacterium classified as a carcinogen. H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. The scenario for the development of gastric adenocarcinoma is similar to that of HBV- and HCV-induced liver cancer. It involves increased epithelial cell

proliferation in a background of chronic inflammation

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General  schema  of  events  in  chemical  carcinogenesis.  Note  that promoters  cause  clonal  expansion  of  the  initiated  cell,  thus  producing  a preneoplastic clone. Further proliferation induced by the promoter or other factors  causes  accumulation  of  additional  mutations  and  emergence  of  a malignant tumor

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