Patho PP on Cancer

Principles of Neoplasia And Growth Disorders

Dr: Wael H Mansy, MDAssistant Professor

Clinical Pharmacy Department-College of Pharmacy

King Saud University

• List the main characteristics of benign and malignant tumors. • Describe the nomenclature used for various types of tumors. • Discuss tumor metastasis. How do tumors facilitate their own spread? What are some common sites of metastasis for tumors? • Define oncogenesis. Discuss some of the theories of how it might occur. List some viruses that are oncogenic, as well as the cancers they may cause.

Study objectives

• What is a carcinogen? List some substances that are carcinogenic. • List the local and systemic effects of cancer. • Define cancer cachexia. Why might it occur? • Describe the system by which tumors are “staged.” • What are tumor cell markers? How are they used clinically? • Discuss the various treatment options for cancer. Include the draw-backs of each.

The term neoplasm refers to an abnormal mass of tissue in which the growth exceeds and is uncoordinated with that of the normal tissues. Unlike normal cellular adaptive processes such as hypertrophy and hyperplasia, neoplasms do not obey the laws of normal cell growth. They serve no useful purpose, they do not occur in response to an appropriate stimulus and they continue to grow at the expense of the host.

The process of cell growth and division is called the cell cycle. It is divided into four phases: 1-G1, the postmitotic phase, during which DNA synthesis ceases while RNA and protein synthesis and cell growth take place; 2-S the phase during which DNA synthesis occurs, giving rise to two separate sets of chromosomes;

Cell Cycle

3-G2 phase: the premitotic phase, during which RNA and protein synthesis continues; 4-M: the phase of cell mitosis or cell division. 5-G0 phase: is a resting or quiescent phase in which nondividing cells reside. The entry into and progression through the various stages of the cell cycle are controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors

oNormal tissue renewal and repair involves cell proliferation, differentiation and apoptosis. oProliferation, or the process of cell division, is an inherent adaptive mechanism for cell replacement when old cells die or additional cells are needed.oDifferentiation is the process of specialization whereby new cells acquire the structure and function of the cells they replace. oApoptosis is a form of programmed cell death that eliminates senescent cells, cells with damaged DNA, or unwanted cells.

Body cells can be divided into two large groups: the well differentiated neurons and cells of skeletal and cardiac muscle that rarely divide and reproduce.The progenitor or parent cells that continue to divide and reproduce, such as blood cells, skin cells, and liver cells. A third category of cells are the stem cells that remain quiescent until there is a need for cell replenishment, in which case they divide, producing other stem cells and cells that can carry out the functions of differentiated cells.

Stem cells have two important properties, those of self-renewal and potency. Self-renewal means that the stem cells can undergo numerous mitotic divisions while maintaining an undifferentiated state. The term potency is used to define the differentiation potential of stem cells.

A neoplasm, benign or malignant, represents a newgrowth.■ Benign neoplasms are well-differentiated tumorsthat resemble the tissues of origin but have lost theability to control cell proliferation. They grow byexpansion, are enclosed in a fibrous capsule, and donot cause death unless their location is such that itinterrupts vital body functions.

■ Malignant neoplasms are less well-differentiated tumors that have lost the ability to control both cell proliferation and differentiation. They grow in a disorganized and uncontrolled manner to invade surrounding tissues, have cells that break loose and travel to distant sites to form metastases, and inevitably cause suffering and death unless their growth can be controlled through treatment.

Cancer Cell Characteristics

Cancer cells are characterized by two main features: (1) abnormal and rapid proliferation; and (2) loss of differentiation so that they do not exhibit normal features and properties of differentiated cells, and hence are more similar to embryonic cells.

Means loss of cell differentiation in cancerous tissue. In undifferentiated cancer cells both the cells and nuclei display variations in size and shape, a condition referred to as pleomorphism. Their nuclei are variable in size and bizarre in shape, their chromatin is coarse and clumped, and their nucleoli are often considerably larger than normal.

ANAPLASIA

Some cancers display only slight anaplasia, whereas others display marked anaplasia. The cytologic/histologic grading of tumors is based on the degree of differentiation and the number of proliferating cells. The closer the tumor cells resemble comparable normal tissue cells, both morphologically and functionally, the lower the grade. Accordingly, on a scale ranging from grades I to IV, grade I neoplasms are well differentiated and grade IV are poorly differentiated and display marked anaplasia.

Cancer Cell Characteristics

1-Genetic Instability.

• Most cancer cells exhibit a characteristic called genetic instability that is often considered to be a hallmark of cancer.

• It is thought that cancer cells have a “mutation phenotype” with genetic instability that contributes to the development and progression of cancer.

Characteristics of genetic instability include aneuploidy, in which chromosomes are lost or gained; intrachromosomal instability, which includes insertions, deletions, and amplifications; microsatellite instability, which involves short,repetitive sequences of DNA; and point mutations.

2-Growth Factor Independence• *The ability to proliferate even in the absence of growth

factors. This characteristic is often observed when cancer cells are propagated in cell culture.

• *The addition of serum, which is rich in growth factors, is unnecessary for the cancers to proliferate.

• *Breast cancer cells that do not express estrogen receptors are an example. These cancer cells grow even in the absence of estrogen, Some cancer cells may produce their own growth factors and secrete them into the culture medium, whereas others have abnormal receptors or signaling proteins

• Q: Give at least 3 examples of Cancer Growth Factors?

3- Cell Density–Dependent Inhibition

• Cancer cells often lose cell density–dependent inhibition.• cells often stop growing when they come into contact with

each other e.g wound healing• Cancer cells, however, tend to grow rampantly without

regard for adjacent tissue. • Possible explanations of this include growth factor

independence, oxidative mechanisms, and alterations in interactions between cell adhesion and cell growth signaling pathways (e.g., surface integrin receptors, mitogen-activated protein [MAP] kinase, and focal adhesion kinase [FAK] phosphorylation)

4- Cell Cohesiveness and Adhesion

The reduced tendency of cancer cells to stick together. These cells appear in the surrounding body fluids or

secretions and often can be detected using cytologic methods. cadherins are adhesion molecules that link one cell with

adjacent cell.

In some cancers, E-cadherin appears to play an important role in the lack of cohesiveness of cancer cells and the increased tendency for cancer cells to break free and migrate into the surrounding tissues.

5- Anchorage Dependence.

• Cancer cells also differ from their normal counterparts in attaining anchorage independence.

• Normal epithelial cells must be anchored to either neighboring cells or the underlying extracellular matrix to live and grow. If these cells become detached, they often undergo a type of apoptosis known as anoikis.

• Cancer cells, however, frequently remain viable and multiply without normal attachments to other cells and the extracellular matrix.

6- Cell-to-Cell Communication

• Impaired cell-to-cell communication may interfere with formation of intercellular connections and responsiveness to membrane derived signals.

• For example, changes in gap junction proteins which enable cytoplasmic continuity and communication between cells, have been described in some types of cancer.

7- Life Span.

• Cancer cells differ from normal cells by being immortal, with an unlimited life span.

• cancer cells may divide an infinite number of times, hence achieving immortality.

• Most cancer cells maintain high levels of telomerase, an enzyme that prevents telomere shortening.

• Telomeres are short, repetitive nucleotide sequences at outermost extremities of chromosome arms

• Telomeres shorten with each cell division. When length is diminished sufficiently, chromosomes can no longer replicate, and cell division will not occur.

8- Antigen Expression

• Cancer cells also express a number of cell surface molecules or antigens that are immunologically identified as foreign.

• Many transformed cancer cells revert to embryonic patterns of gene expression and produce antigens that are immunologically distinct from the antigens that are expressed by cells of the well-differentiated tissue from which the cancer originated.

• Tumor antigens may be clinically useful as markers to indicate the presence, recurrence, or progressive growth of a cancer.

9- Production of Enzymes, Hormones, and Other Substances.

• Cancer cells may produce substances that normal cells of the tissue of origin either do not produce or secrete in lesser amounts.

• Cancer cells may also assume hormone synthesis or production and secretion of procoagulant substances that affect clotting mechanisms.

10- Cytoskeletal Changes.

• Finally, cancer cells may show cytoskeletal changes and abnormalities.

• These may involve the appearance of abnormal intermediate filament types or changes in actin filaments and microtubules that facilitate invasion and metastasis.

Pathophysiology

Invasion and metastasis

• Unlike benign tumors, which grow by expansion and usually are surrounded by a capsule, cancer spreads by direct invasion and extension, seeding of cancer cells in body cavities, and metastatic spread through the blood or lymph pathways.

• Most cancers synthesize and secrete enzymes that break down proteins and contribute to the infiltration, invasion, and penetration of the surrounding tissues.

Invasion and metastasis

• The lack of a sharp line of demarcation separating them from the surrounding tissue makes the complete surgical removal of malignant tumors more difficult than removal of benign tumors.

• Often it’s necessary for the surgeon to excise some of the normal tissues surrounding the cancerous tumor to make sure that the remaining tissues will be cancer free.

• The seeding of cancer cells into body cavities occurs when a tumor sheds cells into these spaces. Most often, the peritoneal cavity is involved, but other spaces such as the pleural cavity, pericardial cavity, and joint spaces may be involved.

• Similar to tissue culture, tumors in these sites grow in masses and are often associated with fluid accumulation (e.g. ascites, pleural effusion).

• The seeding of cancers is often a concern during the surgical removal of cancers where it is possible inadvertently to introduce free cancer cells into a body cavity such as the peritoneal cavity

• The term metastasis is used to describe the development of a secondary tumor in a location distant from the primary tumor.

• Because metastatic tumors frequently retain many of the characteristics of the primary tumor from which they were derived, it’s usually possible to determine the site of the primary tumor from the cellular characteristics of the metastatic tumor.

• Some tumors tend to metastasize early in their developmental course, whereas others do not metastasize until later.

• Occasionally, a metastatic tumor will be found far advanced before the primary tumor becomes clinically detectable e.g Hypernephroma (malignant tumors of the kidney)

• To metastasize, a cancer cell must be able to break loose from the primary tumor, invade the surrounding extracellular matrix, gain access to a blood vessel, survive its passage in the bloodstream, emerge from the bloodstream at a favorable location, invade the surrounding tissue, begin to grow, and establish a blood supply.

• Metastasis occurs through the lymph channels (i.e., lymphatic spread) and the blood vessels (i.e., hematogenic spread).

Lymphatic Spread

• In many types of cancer, the first evidence of disseminated disease is the presence of tumor cells in the lymph nodes that drain the tumor area.

• When metastasis occurs by the lymphatic route, the tumor cells lodge first in the initial lymph node that receives drainage from the tumor site.

• The cancer cells may spread from more distant lymph nodes to the thoracic duct, and then gain access to the vasculature.

• Cancer cells also may gain access to the vasculature from the initial node and more distant lymph nodes through tumor-associated blood vessels infiltrating the tumor mass.

• The term sentinel node is used to describe the initial lymph node to which the primary tumor drains.

• lymphatic spread and therefore extent of disease may be determined through lymphatic mapping and sentinel lymph node biopsy.

• Once the sentinel lymph node has been identified, it is examined to determine the presence or absence of cancer cells.

Hematologic Spread

• The blood-borne cancer cells may enter the venous flow that drains the site of the primary neoplasm.

• Cancer cells may also enter tumor-associated blood vessels that either infiltrate the tumor or are found at the periphery of the tumor.

• Before entering the general circulation, venous blood from the gastrointestinal tract, pancreas, and spleen is routed through the portal vein to the liver. The liver is therefore a common site for metastatic spread of cancers that originate in these organs.

• Although the site of hematologic spread usually is related to vascular drainage of the primary tumor, some tumors metastasize to distant and unrelated sites.

• One explanation is that cells of different tumors tend to metastasize to specific target organs that provide suitable microenvironments containing substances such as cytokines or growth factors that are needed for their survival e.g. transferrin, a growth-promoting substance isolated from lung tissue, has been found to stimulate the growth of malignant cells that typically metastasize to the lungs.

• Considerable evidence suggests that cancer cells capable of metastasis secrete enzymes that break down the surrounding extracellular matrix, allowing them to move through the degraded matrix and gain access to a blood vessel.

• Once in the circulation, the tumor cells are vulnerable to destruction by host immune cells. Some tumor cells gain protection from the antitumor host cells by aggregating and adhering to circulating blood components, particularly platelets, to form tumor emboli.

• Tumor cells that survive their travel in the circulation must be able to halt their passage by adhering to the vessel wall. Tumor cells express various cell surface attachment factors such as laminin receptors that facilitate their anchoring to laminin in the basement membrane.

• After attachment, the tumor cells secrete proteolytic enzymes such as type IV collagenase that degrade the basement membrane and facilitate the migration of the tumor cells through the capillary membrane into the interstitial area, where they subsequently establish growth of a secondary tumor.

• Once in the distant tissue site, the process of metastatic tumor development depends on the establishment of blood vessels and specific growth factors that promote proliferation of the tumor cells. Tumor cells as well as other cells in the microenvironment secrete factors that enable the development of new blood vessels within the tumor, a process termed angiogenesis.

Q: Enumerate at least 2 angiogenic factors?• The presence of stimulatory or inhibitor growth factors correlates

with the site-specific pattern of metastasis. For example, a potent growth-stimulating factor has been isolated from lung tissue, and stromal cells in bone have been shown to produce a factor that stimulates growth of prostatic cancer cells.

• Once cells have an adequate blood supply, the rate of tissue growth in normal and cancerous tissue depends on three factors:

1) The number of cells that are dividing through the cell cycle.2) The duration of the cell cycle.3) The number of cells that are being lost relative to the number of

new cells being produced.

• One of the reasons cancerous tumors often seem to grow so rapidly relates to the size of the cell pool that is actively engaged in cycling.

• cancer cells do not die on schedule and growth factors prevent cells from exiting the cycle cell and entering the G0 phase. Thus, a greater percentage of cells are actively engaged in cycling than occurs in normal tissue.

Tumor growth

• The ratio of dividing cells to resting cells in a tissue mass is called the growth fraction. The doubling time is the length of time it takes for the total mass of cells in a tumor to double. As the growth fraction increases, the doubling time decreases.

• When normal tissues reach their adult size, equilibrium between cell birth and cell death is reached. Cancer cells, however, continue to divide until limitations in blood supply and nutrients inhibit their growth. When this happens, the doubling time for cancer cells decreases.

• a tumor usually is undetectable until it has doubled 30 times and contains more than 1 billion cells. At this point, it is approximately 1 cm. After 35 doublings, the mass contains more than 1 trillion cells, which is a sufficient number to kill the host.

Tumor growth

Etiology of Cancer• The causes of cancers are very diverse and complex. It is useful to

discuss causation in terms of

(1)The genetic and molecular: mechanisms that are involved and that characterize the transformation of normal cells to cancer cells.

(2) The external and more contextual factors such as age, heredity, and environmental agents that contribute to the development and progression of cancer. Together, both mechanisms contribute to a multidimensional web of causation by which cancers develop and progress over time.

Genetic and Molecular Basis of Cancer

Genetic and Molecular Basis of Cancer

The molecular pathogenesis of most cancers is thought to originate with genetic damage or mutation with resultant changes in cell physiology that transform a normally functioning cell into a cancer cell

Cancer-Associated Genes

• Most cancer-associated genes can be classified into two broad categories based on both increases the risk for cancer

• 1) gene over-activity

• 2) gene under-activity


• The category associated with gene over-activity is

proto-oncogenes (which are normal genes that become cancer-causing oncogenes if mutated ) Proto-oncogenes encode for normal cell proteins such as growth factors, growth factor receptors and transcription factors

• The category associated with gene under-activity comprises the tumor suppressor genes .


• Tumor suppressor genes include1) retinoblastoma (RB) gene (which normally prevents cell

division ): Loss of RB activity may accelerate the cell cycle and lead to increased cell proliferation.

2) the TP53 gene (which normally becomes activated in

DNA-damaged cells to initiate apoptosis ) : inactivity of TP53 may increase the survival of DNA-damaged cells.

Genetic Events Leading to Oncogene Formation or ActivationI-Point mutation : a common event is a in which there is a

single nucleotide base change due to an insertion, deletion, or substitution.

An example of an oncogene caused by point mutations is the

ras oncogene, which has been found in many cancers

• Members of the ras proto-oncogene family are important signal-relaying proteins that transmit growth signals to the nucleus, so activation of the ras oncogene can increase cell proliferation.

Genetic Events Leading to Oncogene Formation or ActivationII-Chromosomal translocations have traditionally

been associated with cancers such as Burkitt lymphoma and chronic myelogenous leukemia (CML).

In Burkitt lymphoma, the myc proto-oncogene, which encodes a growth signal protein, is translocated from its normal position on chromosome 8 to chromosome 14, placing it at the site of an immunoglobulin gene.

in CML The outcome of the translocation is the appearance of the so-called Philadelphia chromosome involving chromosomes 9 and 22 and the formation of an abnormal fusion protein that promotes cell proliferation

Genetic Events Leading to Oncogene Formation or Activation

III-Gene amplification: Multiple copies of certain genes may lead to over-expression, with higher-than-normal levels of proteins that increase cell proliferation. For example, the human epidermal growth factor receptor-2 (HER-2/neu) gene is amplified in up to 30% of breast cancers.

Genetic Events Leading to Loss of Tumor Suppressor Gene Function

Tumor suppressor genes inhibit the proliferation of cells in a tumor. When this type of gene is inactivated, a genetic signal that normally inhibits cell proliferation is removed, thereby causing unregulated growth to begin

• TP53 gene located on the short arm of chromosome 17, it codes for the p53 protein, which functions as a suppressor of tumor growth.

• Mutations in the TP53 gene have been implicated in the development of lung, breast, and colon cancer

• The TP53 gene also appears to initiate apoptosis in radiation- and chemotherapy-damaged tumor cells. Thus, tumors that retain normal TP53 function are more likely to respond to such therapy than tumors that carry a defective TP53 gene.


• the malfunction of tumor suppressor genes may require “two hits” to contribute to total loss of function, as suggested by the two-hit hypothesis of carcinogenesis

• The first “hit” may be a point mutation in an allele of a particular chromosome; later, a second “hit” occurs that involves the companion allele of the gene


• In persons carrying an inherited mutation, such as a mutated RB allele, all somatic cells are perfectly normal, except for the increased risk of developing cancer.

• That person is said to be heterozygous at the gene locus. Cancer develops when a person becomes homozygous for the mutant allele, a condition referred to as loss of heterozygosity

Epigenetic Mechanisms

• In addition to mechanisms that involve DNA and chromosomal structural changes, there are molecular and cellular mechanisms, termed epigenetic mechanisms, that involve changes in the patterns of gene expression without a change in the DNA

• Epigenetic mechanisms may “silence” genes, such as tumor suppressor genes, so that even though the gene is present, it is not expressed and a cancer-suppressing protein is not made.

Epigenetic Mechanisms

• Genes silenced by hypermethylation can be inherited, and epigenetic silencing of genes can be considered a first “hit” in the two-hit hypothesis described previously.

• The epigenetic mechanisms that alter expression of genes associated with cancer are under intensive investigation, as are hypomethylating drugs to prevent or treat cancer.

Molecular and Cellular Pathways

There are numerous molecular and cellular mechanisms with a endless of associated pathways and genes that are known or suspected to facilitate the development of cancer. Here is some examples from the author of the text book .

1- DNA Repair Defects.2- Defects in Growth Factor Signaling Pathways.3- Evasion of Apoptosis.4- Evasion of Cellular Senescence.5- Development of Sustained Angiogenesis.6- Invasion and Metastasis.

1- DNA Repair Defects

Genetic mechanisms that regulate repair of damaged DNA have been implicated in the process of oncogenesis

(Fig. 8-7)

NEXT SLID

DNA Repair Defects (Fig. 8-7)

DNA Repair DefectsThe DNA repair genes affect cell proliferation and

survival indirectly through their ability to repair nonlethal damage in proto-oncogenes, tumor suppressor genes and genes that control apoptosis.

These genes is the principal targets of genetic damage occurring during the development of a cancer.

Genetic damage may be caused by the action of chemicals, radiation, or viruses.

2- Defects in Growth Factor Signaling Pathways

Definition : A relatively common way in which cancer cells gain autonomous growth is through mutations in genes that control growth factor signaling pathways.

Growth Factor Signaling Pathways Under Normal Conditions

Note : Cell proliferation involves the binding of a growth factor to its receptor on the cell membrane .

Activation of the growth factor receptor on the inner surface of the cell membrane . Transfer of the signal across the cytosol to the nucleus by signal-transducing proteins (as second messengers) . Induction and activation of regulatory factors that initiate DNA transcription, and entry of the cell into the cell cycle (Fig. 8-8)

Growth Factor Signaling Pathways Under Normal Conditions

Many of the proteins involved in the signaling pathways that control the action of growth factors exert their effects through kinases, enzymes that phosphorylate proteins.

• In CML, mutation in a proto-oncogene controlling tyrosine kinase activity occurs, causing unregulated cell growth and proliferation

• Q: What is the name of this proto-oncogene?

3-Evasion Of Apoptosis

The failure of cancer cells to undergo apoptosis in a normal manner may be due to a number of problems :

• There may be altered cell survival signaling .• Over active Ras proteins .• TP53 mutations .• Down-regulation of death receptors.• Stabilization of the mitochondria .• Inactivation Of Proapoptotic Proteins (E.G., Methylation Of Caspase-

8).• Overactivity of nuclear factor kappa B (Nf-êb) .• Heat-shock Protein Production.• Failure Of Immune Cells To Induce Cell Death.

Evasion Of Apoptosis

Example : the high levels of the antiapoptotic protein Bcl-2 thatoccur secondary to a chromosomal translocation in certainB-cell lymphomas. The mitochondrial membrane is a key regulatorof the balance between cell death and survival. Proteins in the Bcl-

2 family reside in the inner mitochondrial membraneand are either proapoptotic or antiapoptotic. Because apoptosis is

considered a normal cellular response to DNA damage, loss of normal apoptotic pathways may contribute to cancer by enabling DNA-damaged cells to survive.

Facts

27 Alterations in apoptotic and antiapoptotic pathways, genes, and proteins have been

found in many cancers.

4- Evasion Of Cellular Senescence

• It is another normal cell response to DNA damage.

• As cancer cells are characterized by immortality due to high levels of telomerase that prevent cell aging and hence senescence (aging), thus high levels of telomerase and prevention of telomere shortening may also contribute to cancer and its progression.

• Because senescence is considered to be a normal response to DNA damage in cells as well as a tumor suppressor mechanism.

5- Development of Sustained Angiogenesis

Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels.

Even with all the aforementioned genetic abnormalities, tumors cannot enlarge unless angiogenesis occurs and supplies them with the blood vessels necessary for survival.

it is required for continued tumor growth & metastasis

The molecular basis for the angiogenic switch is unknown

The normal TP53 gene seems to inhibit angiogenesis by inducing the synthesis of an antiangiogenic molecule called thrombospondin-1 .

With mutational inactivation of both TP53 alleles (as occurs in many cancers), the levels of thrombospondin-1 drop markedly, tilting the balance in favor of angiogenic factors.

Angiogenesis is also influenced by hypoxia and release of proteases that are involved in regulating the balance between angiogenic and antiangiogenic factors.

Facts

Because of the crucial role of angiogenic factors in tumor growth, much interest is focused on the development of antiangiogenesis therapy.

Antiangiogenesis therapy is showing synergistic antitumor actions when combined with conventional forms of chemotherapy in the treatment of certain cancers

Q: Enumerate two antiagiogenic drugs and their uses?

Invasion and Metastasis

Finally, multiple genes and molecular and cellular pathways are known to be involved in invasion and metastasis.

There is evidence that cancer cells with invasive properties are actually members of the cancer stem cell population discussed previously.

This evidence suggests that genetic programs that are normally operative in stem cells during embryonic development may become operative in cancer stem cells, enabling them to detach, cross tissue boundaries, escape death by anoikis ( is a form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM)), and colonize new tissues.

The MET protooncogenewhich is expressed in both stem cells and cancer cells, is a key regulator of invasive growth.

Recent findings suggest that adverse conditions such as tissue hypoxia, which are commonly present in cancerous tumors, trigger this invasive behavior by activating the MET tyrosine kinase receptor.

Q:What is the main protein synthesized by MET gene?

Role of the Microenvironment

The microenvironment of the cancer cell consists of multiple cell types including :

-Macrophages, fibroblasts, endothelial cells, variety of immune and inflammatory cells, the extracellular matrix, and the primary signaling substances such as cytokines, chemokines and hormones.

-The essential steps needed for tumor growth and metastasis, such as angiogenesis and metastatic tumor survival, depend on the microenvironment.

Carcinogenesis

The process by which carcinogenic (cancer-causing) agents cause normal cells to become cancer cells is hypothesized to be a multistep mechanism that can be divided into three stages:

• initiation• promotion• progression

(Fig. 8-9)

Initiation

involves the exposure of cells to appropriate doses of a carcinogenic agent that makes them susceptible to malignant transformation.

The carcinogenic agents can be: • Chemical.• physical.• Biologic.and produce irreversible changes in the genome of a previously

normal cell. Fact

The cells most susceptible to mutagenic alterations are those that are actively synthesizing DNA.

Promotion

involves the induction of unregulated accelerated growth in already initiated cells by various chemicals and growth factors.

Promotion is reversible if the promoter substance is removed.

Facts Cells that have been irreversibly initiated may be promoted even

after long latency periods. Many chemical carcinogens are called complete carcinogens

because they can initiate and promote neoplastic transformation.

Q: Give 2 examples of complete carcinogens?

Progression

is the process whereby tumor cells acquire malignant phenotypic changes :

promote invasiveness. metastatic competence. autonomous growth tendencies. increased karyotypic instability.

Host and Environmental Factors

Host and Environmental Factors

The cancer is not a single disease, it is reasonable to assume

that it does not have a single cause. More likely, cancer occurs

because of interactions among multiple risk factors or repeated

exposure to a single carcinogenic agent. Among the traditional

risk factors that have been linked to cancer are heredity, hormonal

factors, immunologic mechanisms, and environmental

agents such as chemicals, radiation, and cancer-causing viruses.

More recently, there has been interest in obesity as a risk factor

for cancer.

Heredity

*A hereditary predisposition to approximately 50 types of cancer has been observed in families.

*Breast cancer, for example, occurs more frequently in women whose grandmothers, mothers, aunts, or sisters also have experienced a breast malignancy.

*Two tumor suppressor genes, called BRCA1 (breast cancer susceptibility gene1) and BRCA2 (breast cancer susceptibility gene2) have been implicated in genetic susceptibility to breast cancer.

*Individuals carrying a BRCA mutation have a lifetime risk (if they live to the age of 85 years) of 80% for developing breast cancer. The lifetime risk for developing ovarian cancer is 10% to 20% for carriers of BRCA2 mutations and 40% to 60% for BRCA1 mutations.

• Several cancers exhibit an autosomal dominant inheritance pattern that greatly increases the risk of developing a tumor.

• Retinoblastoma, a rare childhood tumor of the retina, is an example of a cancer that follows an autosomal dominant inheritance pattern. Approximately 40% of retinoblastomas are inherited, and carriers of the mutant RB tumor suppressor gene have a 10,000-fold increased risk for developing retinoblastoma, usually with bilateral involvement.

The inherited mutation is usually a point mutation occurring in a single allele of a tumor suppressor gene.

Hormones

Hormones have received considerable research attention with respect to cancer of the breast, ovary, and endometrium in women and of the prostate and testis in men.

Although the link between hormones and the development of cancer is unclear, it has been suggested that it may reside with the ability of hormones to drive the cell division of a malignant phenotype.

Because of the evidence that endogenous hormones affect the risk of these cancers, concern exists regarding the effects on cancer risk if the same or closely related hormones are administered for therapeutic purposes.

Immunologic Mechanisms

• The central concept, known as the immune surveillance hypothesis, first proposed by Paul Ehrlich in 1909, postulates that the immune system plays a central role in resistance against the development of tumors.

• In addition to cancer–host interactions as a mechanism of cancer development, immunologic mechanisms provide a means for the detection, classification, and prognostic evaluation of cancers and as a potential method of treatment.

• Cancer might be associated with impairment or decline in the surveillance capacity of the immune system.

1-Cancer incidence increases in people with immunodeficiency diseases e.g. association of Kaposi sarcoma with AIDS.

2-Cancer incidence increases in those with organ transplants who are receiving immunosuppressant drugs.

3-Cancer incidence increases in the elderly, in whom there is a known decrease in immune activity.

• It has been shown that most tumor cells have molecular configurations that can be specifically recognized by immune T cells or by antibodies and hence are termed tumor antigens.

The most relevant tumor antigens fall into two categories:

1-Unique, tumor specific antigens found only on tumor cells

2-Tumor-associated antigens found on tumor cells and normal cells.

• Quantitative and qualitative differences permit the use of tumor-associated antigens to distinguish cancer cells from normal cells.3

Chemical carcinogens

Chemical carcinogens can be divided into two groups:

(1) direct-reacting agents, which do not require activation in the body to become carcinogenic.

(2) indirect-reacting agents, called procarcinogens or initiators, which become active only after metabolic conversion.

Direct- and indirect-acting initiators form highly reactive species (i.e., electrophiles and free radicals) that bind with the nucleophilic residues on DNA, RNA, or cellular proteins.

• The action of these reactive species tends to cause cell mutation or alteration in synthesis of cell enzymes and structural proteins in a manner that alters cell replication and interferes with cell regulatory controls

Cont,

• The carcinogenicity of some chemicals is augmented by agents called promoters that, by themselves, have little or no cancer-causing ability. It is believed that promoters exert their effect by changing the expression of genetic material in a cell, increasing DNA synthesis, enhancing gene amplification.

• Exposure to many chemical carcinogens is associated with lifestyle risk factors, such as smoking, dietary factors, and alcohol consumption.

• Cigarette smoke contains both procarcinogens and promoters. It is directly associated with lung and laryngeal cancer and has been linked with cancers of the mouth, nasal cavities, pharynx, esophagus, pancreas, liver, kidney, uterus, cervix, and bladder, and with myeloid leukemias.

• Chewing tobacco or tobacco products increases the risk of cancers of the oral cavity and esophagus. It has been estimated that 30% of all cancer deaths and 87% of lung cancer deaths in the United States are related to tobacco.36 Not only is the smoker at risk, but others passively exposed to cigarette smoke are at risk.

• Environmental tobacco smoke has been classified as a “group A” carcinogen based on the U.S. Environmental Protection Agency’s system of carcinogen classification. Each year, about 3000 nonsmoking adults die of lung cancer as a result of environmental tobacco smoke.

• There is strong evidence that certain elements in the diet contain chemicals that contribute to cancer risk.

• Most known dietary carcinogens occur either naturally in plants (e.g., aflatoxins) or are produced during food preparation.

• The effects of carcinogenic agents usually are dose dependent—the larger the dose or the longer the duration of exposure.

• List of carcinogens at page 175.

Radiation

• The effects of ionizing radiation in carcinogenesis have been well documented in atomic bomb survivors, and in industrial workers, scientists, and physicians who were exposed during employment. Malignant epitheliomas of the skin and leukemia were significantly elevated in these populations.

• The type of cancer that developed depended on the dose of radiation, the sex of the person, and the age at which exposure occurred.For example, children exposed to ionizing radiation in utero have an increased risk for developing leukemias and childhood tumors, particularly 2 to 3 years after birth. This latency period for leukemia extends to 5 to 10 years if the child was exposed after birth and to 20 years for certain solid tumors

• The association between sunlight and the development of skin cancer has been reported for more than 100 years.

• Ultraviolet radiation plays a role causing skin cancer primarily on the areas of skin more frequently exposed to sunlight (e.g., the head and neck, arms, hands, and legs), a higher incidence in light-complexioned individuals who lack the ultraviolet-filtering skin pigment melanin, and the fact that the intensity of ultraviolet exposure is directly related to the incidence of skin cancer, as evidenced by higher rates occurring in Australia and the American Southwest.

Oncogenic Viruses

Four DNA viruses have been implicated in human cancers:

the human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human herpesvirus-8 (HHV8).

HHV-8, which causes Kaposi sarcoma in persons with AIDS.

• There are over 60 genetically different types of HPV. Some types (i.e., types 1, 2, 4, 7) have been shown to cause benign squamous papillomas (i.e., warts).

• HPVs also have been implicated in squamous cell carcinoma of the cervix and anogenital region. HPV types 16 and 18 and, less commonly, HPV types 31, 33, 35, and 51 are found in approximately 85% of squamous cell carcinomas of the cervix and presumed precursors (i.e., severe cervical dysplasia and carcinoma in situ).

• EBV is a member of the herpes virus family. It has been implicated in the pathogenesis of four human cancers: Burkitt lymphoma, nasopharyngeal cancer, B-cell lymphomas in immunosuppressed individuals such as those with AIDS, and in some cases of Hodgkin lymphoma.

• HBV is the etiologic agent in the development of hepatitis B, cirrhosis, and hepatocellular carcinoma. There is a significant correlation between elevated rates of hepatocellular carcinoma worldwide and the prevalence of HBV carriers.

Cont,

• Although there are a number of retroviruses (RNA viruses) that cause cancer in animals, human T-cell leukemia virus-1 (HTLV-1) is only known retrovirus to cause cancer in humans.

• HTLV-1 is associated with a form of T-cell leukemia that is endemic in parts of Japan and some areas of the Caribbean and Africa, and is found sporadically elsewhere, including the Unit States.

Cont,

There probably is not a single body function left unaffected by the presence of cancer.

Because tumor cells replace normally functioning parenchymal tissue, the initial manifestations of cancer usually reflect the primary site of involvement.

For example, cancer of the lung initially produces impairment of respiratory function; as the tumor grows and metastasizes, other body structures become affected.

Tissue Integrity

Cancer disrupts tissue integrity. As cancers grow, they compress and erode blood vessels, causing ulceration and necrosis along with frank bleeding and sometimes hemorrhage.

One of the early warning signals of colorectal cancer is blood in the stool. Cancer cells also may produce enzymes and metabolic toxins that are destructive to the surrounding tissues. Usually, tissue damaged by cancerous growth does not heal normally.

Instead, the damaged area persists and often continues to grow; a sore that does not heal is another warning signal of cancer.

Cancer has no regard for normal anatomic boundaries; as it grows, it invades and compresses adjacent structures. Abdominal cancer, for example, may compress the viscera and cause bowel obstruction.

Cont,

The development of effusions (i.e., fluid)

in the pleural, pericardial, or peritoneal spaces may be the presenting sign of some tumors.

Direct involvement of the serous surface seems

to be the most significant inciting factor,

although many other mechanisms, such as obstruction of lymphatic flow, may play a role.

• The production of glucose (gluconeogenesis) from lactate uses adenosine triphosphate (ATP) and is very energy inefficient, contributing to the hypermetabolic state of cachectic patients.

• Another mechanism for the increasing energy expenditure in cachectic persons is the increased expression of mitochondrial uncoupling proteins that uncouple the oxidative phosphorylation process, so that energy is lost as heat.

Fatigue and Sleep Disorders

Anemia

Paraneoplastic Syndromes

• In addition to signs and symptoms at the sites of primary and metastatic disease, cancer can produce manifestations in sites that are not directly affected by the disease.

• Such manifestations are collectively referred to as paraneoplastic syndromes.

• Some of these manifestations are caused by the elaboration of hormones by cancer cells, and others from the production of circulating factors that produce hematopoietic, neurologic, and dermatologic syndromes (Table1).

• A wide variety of cutaneous syndromes is associated with malignancies and may precede, be concurrent with, or follow the discovery of cancer.

• Among the paraneoplastic dermatologic disorders is acanthosis nigricans, characterized by pigmented hyperkeratoses that occur in skin flexures, particularly the axillary and perineal areas.The lesions may be accompanied by pruritus.

• The condition is usually associated with adenocarcinomas of the gastrointestinal tract, particularly gastric carcinoma, but may be associated with a variety of adenocarcinomas, including lung, breast, ovarian, and even hematologic cancers.

• The pathogenesis of these lesions is uncertain.

Screening

• Screening represents a secondary prevention measure for the early recognition of cancer in an otherwise asymptomatic population.

• It requires a test that will specifically detect early cancers or pre-malignancies, is cost effective, and results in improved therapeutic outcomes.

• More sensitive screening methods such as tumor markers are being developed for these forms of cancer.

Cancers for which current screening or early detection has led to improvement in outcomes include:

1-Cancer of the breast (breast self-examination and mammography)

2-Cancer cervix (Pap smear).

3-Colo-rectal cancer (rectal examination, fecal occult blood test, and flexible sigmoidoscopy and colonoscopy)

4-Cancer prostate (prostate specific antigen [PSA] testing and transrectal ultrasonography).

Diagnosis

1-Tumour Markers.

2-Cytologic and Histologic Methods:

a-Pap smear.

b-Tissue biopsy.

c-Immuno-histochemistry.

d-Microarray Technology.

3-Staging and Grading of Tumors

Tumour Markers

• Tumor markers are antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor.

• Tumor markers are used for screening, establishing prognosis, monitoring treatment, and detecting recurrent disease.

• The serum markers that have proved most useful in clinical practice are human chorionic gonadotropin (hCG), CA-125, PSA, α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and CD blood cell antigens.

• See table page 182

• As diagnostic tools, tumor markers have limitations. Nearly all markers can be elevated in benign conditions, and most are not elevated in the early stages of malignancy.

• Hence, tumor markers have limited value as screening tests. Furthermore, they are not in themselves specific enough to permit a diagnosis of a malignancy, but once a malignancy has been diagnosed and shown to be associated with elevated levels of a tumor marker, the marker can be used to assess response to therapy.

A-Pap Smear

• The Pap test is a cytologic method used for detecting cancer cells.

• It consists of a microscopic examination of a properly prepared slide by a cytotechnologist or pathologist for the purpose of detecting the presence of abnormal cells.

• Although the Pap test is widely used as a screening test for cervical cancer, it can be performed on other body secretions, including nipple drainage, pleural or peritoneal fluid, and gastric washings.

B-Tissue Piopsy

• involves the removal of a tissue specimen for microscopic study.

• Biopsies are obtained in a number of ways, including needle biopsy; endoscopic methods, such as bronchoscopy or cystoscopy, which involve the passage of an endoscope through an orifice and into the involved structure; or laparoscopic methods.

• In some instances, a surgical incision is made from which biopsy specimens are obtained.

• Excisional biopsies are those in which the entire tumor is removed.

• A quick frozen section may be done to determine the nature of a mass lesion or evaluate the margins of an excised tumor to ascertain that the entire neoplasm has been removed.

• Fine-needle aspiration is another approach that is widely used. The procedure involves aspirating cells and attendant fluid with a small-bore needle.

• The method is most commonly used for assessment of readily palpable lesions in sites such as the thyroid, breast, and lymph nodes.

• Modern imaging techniques have also enabled the method to be extended to deeper structures such as the pelvic lymph nodes and pancreas.

C-Immunohistochemistry

• Immunohistochemistry involves the use of antibodies to facilitate the identification of cell products or surface markers.

• Antibodies against intermediate filaments have proved useful because tumor cells often contain intermediate filaments characteristic of their tissue of origin.

• WHY? Because certain anaplastic carcinomas, malignant lymphomas, melanomas, and sarcomas look very similar under the microscop & In cases in which the origin of the metastasis is obscure & to detect molecules that have prognostic or therapeutic significance e.g. detection of estrogen receptors on breast cancer cells.

D-Microarray technology• Microarray technology is a collection of microscopic DNA

spots attached to a solid surface. It is used to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome.

• DNA arrays are now commercially available to assist in making clinical decisions regarding breast cancer treatment.

• Can be used for predicting prognosis and response to therapy, examining tumor changes after therapy, and classifying hereditary tumors.

Staging and Grading

• The two basic methods for classifying cancers are grading according to the histologic or cellular characteristics of the tumor and staging according to the clinical spread of the disease.

• Grading of tumors involves the microscopic examination of cancer cells to determine their level of differentiation and the number of mitoses. Cancers are classified as grades I, II, III, and IV with increasing anaplasia or lack of differentiation.

• The clinical staging of cancer using TNM system of the American Joint Committee on Cancer (AJCC) is used by most cancer facilities.

• the “TNM” system includes a description of tumor size (T), involvement of lymph nodes (N) and metastasis (M).

• The time of staging is indicated as clinical–diagnostic staging (cTNM), postsurgical resection–pathologic staging (pTNM), surgical evaluative staging (sTNM), retreatment staging (rTNM), and autopsy staging (aTNM)

Tumor Staging

• T — Primary tumor (Is there a tumor and if so how big is it?)

• TX — Primary tumor cannot be assessed

• TO — No evidence of primary tumor

• Tis — Carcinoma in situ

• T1–T4 — Increasing size of tumor

Tumor Staging

• N — Involvement of lymph nodes (Has the tumor spread to the lymph nodes?)

• NX — Regional lymph nodes cannot be assessed• NO — No evidence that the tumor has

metastasized to lymph nodes in the region of the primary tumor

• N1–N3 — Progressive involvement of regional lymph nodes

Tumor Staging

• M — Distant metastasis (Has the tumor spread to distant sites in the body?)

• Mx — Distant metastasis cannot be assessed

• MO — No evidence of distant metastasis

• M1— Single or multiple sites of metastasis have been located

Cancer Treatment

• The goals of cancer treatment methods fall into three categories: curative, control, and palliative.

• The most common modalities are surgery, radiation therapy, chemotherapy, hormonal therapy and biotherapy.

• The treatment of cancer involves the use of a carefully planned program that combines the benefits of multiple treatment modalities and the expertise of an interdisciplinary team of specialists.

THANK YOU

Patho PP on Cancer

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