PATHO Exam 2 - Ch 9 Cancer

Oncogenes

- (mutated proto-oncogenes) can cause cancer via overproduction of normal proteins or normal production of altered hyperactive proteins. - Most known oncogenes act by releasing the cell form environmental feedback, thereby allowing the cell to proliferate abnormally. This increased cellular proliferation may occur via abnormal production of growth factor, growth factor receptors, cytoplasmic signaling molecules, and nuclear transcription factors.

Cancer cells are defined by 2 heritable properties

- Autonomy: the cancer cell has independence from normal cellular controls - Anaplasia: is the loss of differentiation

4 categories of proto-oncogenese thatcomponents that promote cell proliferation

- Growth factor - growth factor receptors - cytoplasmic signaling molecules nuclear transcription factors

Bacterial causes of cancer

- Helicobacter pylori - infects more than half of the worlds population - responsible for the majority of cases of gastric lymphomas and gastric carcinomas

Inherited cancer genes

- If genetic events occurs in somatic cells, they are not inherited by future generations. If mutations are carried in the DNA of germ cells, the mutation can be carried by all of the offspring's body cells. - Examples of inherited human cancers & the associated tumor-suppressor gene whose function is lost include: retinoblastoma, wilmis tumor (childhood cancer of the kidney), neurofibromatosis, familial breast cancer/familial colon cancer

Telomerase gene and cancer

- Most cancer cells switch on the telomerase gene as they acquire the malignant phenotype. - The cancer cells now synthesize telomerase and thus rescue themselves from telomere shortening. - The cancer cell is now immortal and continues to divide indefinitely.

Anchorage Dependence

- Normal cells exhibit this, normal cells do not divide unless they are attached to a firm surface. - Cancer cells are often anchorage independent. They will continue to divide even when suspended in a soft agar gell

Mortal vs Immortal

- Normal cells have a limited life span in the lab. Normal cells may divide in a Petri dish 10 or 50 times, but then they cease growing. - Cancer cells usually are immortal. Cancer cells with continue to divide for years under appropriate lab conditions.

Differentiation

- Normal cells: process of acquiring a specialized function and organization (stem cells becomes a muscle cells). - Cancer cells exhibit anaplasia.

Leukemia and Lymphomas

- are malignant tumors or hematopoietic cells - 9% of malignant cells

History of progression of most malignant tumor

- can be divided into 4 phases: - Transformation: is a malignant change in the initiating cell - Growth of transformed cell: - Local invasion: is a prerequisite for metastasis and the first step in the metastatic process. - Distant metastasis

Initiators

- caused by genetic damage

Mechanisms important in local invasion

- cellular proliferation: invasion is dependent on the interplay between cell generation time, number of cells dividing and number of cells being lost from the tumor. - mechanical pressure: pressure from growing mass blocks local BV and the loss of perfusion causes local tissue death. This local tissue death leads to decreased mechanical resistance which aids tumor spread. - angiogenesis and perhaps lymphatogenesis - degestion of capsules and other structural barriers: lytic enzymes secreted by the tumor cells or released by host cells destroy the normal EC matrix & allow tumor to invade. - decreased cell- to-cell adhesion: cancer cells gain ability to move individually. - increased motility of individual tumor cells: Tumor cells become mobile in response to motility factors.

Density inhibition

- contact inhibition - Normal cells cease to divide when they fill a Petri dish - Transformed cell continue to crowd and eventually pile up on top of one another. Transformed cells therefor exhibit a loss of contact inhibition.

Tumor Staging system

- describes how far the cancer has spread anatomically. - Staging involves 1) determining the size of tumor 2) determining the degree to which it has locally invaded 3) determining the extent of metastasis. - tumor staging may be used to determine the most appropriate therapy, with more aggressive therapy delivered to more invasive disease. -

Tumor Grading and staging

- done to predict tumor behavior and to guide therapy. Grade I - tumors a well differentiated. The tumor closely resembles the tissue of origin and retains some specialized function Grade II - tumors are moderately differentiated. The tumor has less resemblance to tissue of origin. More variation in size and shape of tumor cell. greatly increased mitoses. Grade III - tumors are poorly to very poorly differentiated. The tumor does not resemble tissue of origin. More variation in size and shape of tumor cells. Greatly increased mitoses. Grade IV - tumors are very poorly differentiated. The tumor has no resemblance to tissue of origin. Great variation in size and shape of tumor cells.

Promoters

- encourages tumor growth

Function of TSG

- functions are varied, but all tumor suppressor genes appear to inhibit cell proliferation via one of two main mechanisms: inhibition of cell division or induction of apoptosis. - TSG induce apoptosis in defective cells. - p53 protein is the product of a tumor suppressor gene. - p53 thwarts neoplastic transformation by 3 interwoven mechanisms. - a defect in p53 function disrupts the cell's quality control system, allowing genetically damaged/unstable cells to survive and continue to replicate. These genetically unstable cells have a propensisty to accumulate more cancer-promoting mutations as they proliferate. - chemo & radiation agents do not kill cells directly but rather by p53.

Genes implicated in cancer

- genes implicated in cancer are those of cellular control pathways and include genes involved in: - signal transduction - cell cycle control - DNA repair - Cell growth and differentiation - transcriptional regulation - senescence - apoptosis

List of Tumor cell markers (5)

- hormones: hCG is an often-seen tumor marker. Other examples are ACTH and catecholamines. - enzymes - genes: found inside the cell. can often establish a diagnosis - antigens: two examples are carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) - antibodies: development of monoclonal antibody technology has put antibodies near the top of the list as a potentially rewarding category of tumor markers. Hybrid cells can secrete an antibody to a specific tumor antigen.

Kaposi sarcoma

- human cancer linked to viral infections - caused by human herpesvirus-8 - Also known as Kaposi sarcoma herpesvirus (KSHV) - usually occurs in those also infected with HIV-1

Cervical carcinoma

- human cancer linked to viral infections - linked to one of several serotypes of human papillomavirus (HPV) - Gardasil is a vaccine that protects against future infections with HPV but the vaccine does not protect against existing HPV infections.

Liver carcinoma

- human cancer linked to viral infections - up to 80% of liver cancer worldwide is associated with chronic hepatitis caused by hepatitis B virus or hepatitis C virus

Adult T-cell leukemia/lymphoma

- human cancer links to viral infections - caused by the retrovirus human T-cell leukemia-lymphoma virus (HTLV)

Causes of cancer

- include environmental agents, inherited cancer genes, viruses, and bacteria.

Process of carcinogenesis

- initiation - promotion - progression

Burkitt lymphoma

- is a cancer of B cells that is associated with Epstein-Barr virus in areas of endemic malaria.

Nasopharyngeal carcinoma

- is associated with Epstein-Barr virus infection in parts of Asia.

Stability gene (or caretaker genes)

- keep genetic alterations to a minimum; when stability genes are inactivated, mutations in other genes occur at a higher rate. - examples : BRCA1 and BRCA2 (breast cancer)

Transformed cells

- lack many of the normal "social controls" seen in nontransformed cells. - the lack of antisocial properties allow the cancer cells to ignore growth-controlling signals from the environment.

Cancer progression and metastasis

- matastasis is a defining characteristic of cancer - metastasis is the spread of tumor cells from the site of the original tumor to distant tissues and organs throughout the body. - malignant neoplasmas disseminate by one of 3 pathways: seeding within body cavities, lymphatic spread, hematogenous spread. - metastasis contributes significantly to the pain and suffering from cancer. - metastasis is the major cause of death from cancer. While still localized, low stage cancers respond well to a combination of surgery, chemotherapy, and radiation. Once a cancer has metastasized, these same therapies are often ineffective. -

6 acquired capabilities of cancer cells

- most cancers acquire mutations in these 6 distinct areas of cell control during their development. - mutations: - self sufficiency in growth signals - insensitivity to anti-growth signals - evasion of apoptosis - limitless replicative potential - sustained angiogenesis - tissue invasion and metastasis

Stages of progression of development of cancer

- normal cells - low-grade intraepithelial neoplasia - high-grade intraepithelial neoplasia - invasive carcinoma (malignancy)

Mutations that create oncogenes include:

- point mutations: - chromosome translocation (rearrangement) - gene amplification

Expression of Telomerase gene

- possible mechanism of cancer cell immortality - Each time a cell divides, it must replicate is DNA, but DNA polymerase is unable to replicate the DNA located at the end of the chromosomes (telomeres). - At each replication the telomere shortens - a critically small telomere allows the chromosomes with unprotected end caps to become unstable & fragment, leading to cell death - enzyme complex (telomerase) is needed to replicate the telomeres - enzyme is normal only active in certain rapidly-dividing stem cells in skin, bone marrow and gut.

Multi-hit hypothesis

- prevailing view that carcinogenesis has a number of cellular control pathways must be altered for a cell to become fully malignant.

Carcinogenesis & Carcinogens

- process of tumor development - carcinogens applied to agents and substances capable of inducing cancer - carcinogens can be groups into 2 major types: initiators & promoters

Tumor suppressor gene

- puts the brakes on cell proliferation and therefore inactivation of tumor suppressor genes allows unchecked cellular proliferation. - the TSG inactivation route has a recessive effect because both copies of a tumor suppressor gene must be inactivated in order to eliminate its suppressor function. - cancer may arise when tumor suppressor gene function is lost. -

Carcinoma

- refers to malignant tumors of epithelial origin - 90% of malignant tumors - The common carcinomas (lung, breast, colon, prostate) arise in epithelial tissues that are normally engages in a high rate of cell division

Sarcoma

- refers to malignant tumors of transformed cells of mesenchymal (undifferentiated loose connective tissue derived mainly form mesoderm) origin - examples: bone, cartilage, fat, muscle, vascular, or hematopoietic tissues - 1% of malignant tumors

Carcinoma in situ

- refers to preinvasive epithelial tumors of glandular or squamous cell origin.

Promotion

- refers to the stage in which the mutant cell is induced to proliferate by exposure to a tumor promoter. - tumor growth-promoter may not the original mutation - non-mutating factors may also be promoters. These include nutritional factors, infection and hormones. - most evidence supports the role of hormones as promoters rather than as primary carcinogens. - transition from initiation to promotion may involve the activation of a different oncogene or inactivation of a different tumor suppressor gene. - only previously-initiated cells are stimulated to grow.

Growth in the target organ parenchyma

- requires 2 components: development of an adequate blood supply and ineffective host defenses. - Without the development of new blood vessels, tumors would fail enlarge b/c hypoxia would induce apoptosis by activation of p53. - Factors that cause blood vessel formation in a tumor include: vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-alpha. - ineffective host defenses.

Tumor marker uses

- screening a healthy population or a high risk population - make a diagnosis of cancer or help determine the specific type of cancer. - predict patient prognosis - monitor the clinical course in a patient in remission or to determine the response to treatment

Progression

- stage during which the mutant, proliferating cells begin to exhibit malignant behavior. - during progression the proliferating cells undergo malignant conversion. - This process is generally slow, occurs over a long time, and is altered greatly by agents taht affect growth rates. - the majority of malignant cells commonly produce telomerase and have insufficient p53. - the first detailed model of genetic progression was developed for colon cancer.

High-grade intraepithelial neoplasia (carcinoma in situ)

- the cells in all the layers are proliferating and apparently undifferentiated. Squamous epithelium of uterine cervix is a common site for in situ neoplasms.

Oncogenic viruses

- Are true pathogenic agents because they cause a specific type of malignant or benign tumor in susceptible individuals. - Cells infected by these viruses are transformed when the viral oncogene is activated. Infection by this virus however is not enough to cause cancer, there have to be cofactors that increase the risk - many oncogenic DNA viruses encode proteins that bind to RB and render it nonfunctional.

Antisocial behaviors

- Cancer cells proliferate excessively - Cancer cells become immortal - Cancer cells invade locally - Cancer cells my travel to distant sites where they establish new colonies.

Mechanisms that give rise to the observed patterns of metastasis

- Cancer cells spread through vascular and lymphatic pathways. Distant metastasis often takes place in the 1st capilary bed encountered by the circulating cells - main sites of blood-borne metastasis include: bone, brain, liver, lung, adrenal glands - there is a selectivity of differnet cancers for different sites. Some tumors seem to show preferential growth in certain organs, called organ tropism. organ tropism is determined genetically.

Genetic mechanism of cancer

- Cancer is primarily a disorder of gene expression. A diverse array of agents are carcinogenic but all have one property in common: these agents all alter the genome.

Proto-oncogenes

- Codes for components of cellular growth-activating pathways. - becomes inappropriately activated ina precancerous cell. This overactivity enhances cell proliferation and predisposes to the develpment of cancer. - activation route has a dominant effect b/c only one fo the cell's 2 alleles need to mutate. The mutated proto-oncogene is called an oncogene. the unaltered normal allele of that gene is called a proto-oncogene.

4-step theory to describe the sequence of biochemical events during tumor cell invasion of the EC matrix

- Detachment: of tumor cells from each other. Adjacent E-cadherin molecules act as intercellular glue to keep cells together. E-cadherin function is lost in almost all epithelial cancers - degration of ECM. 2nd step in invasion is local degradation of the basement membrane and interstitial conncective tissuee. The tumor cell either secretes proteolytic enzymes or induces host cells to produce proteolytic enzymes. These enzymes degrade the attachment proteins and the structural proteins in the EC matrix. - Attachment to novel ECM components. attachment is mediated by specific attachemnt proteins in the ECM such as fibronectin and laminin. Tumor cells produce cell surface receptors specific for the ECM proteins lamin and fibronectin. Laminin receptors allow tumor cells to attach to the ECM. Laminn forms a bridge between the tumor laminin receptor and type IV collagen in the ECM. - Migration of tumor cells. Fingerlike projections of the tumor cell cross the basement membrane, enabling the cell to extravaste from the BV into the IS fluid,

Immunity and cancer

- The role of the immune system in cancer development is complex. A protective role of immune surveillance is true for viral-induced cancer but not for the most prevalent cancers such as breast, prostate, and colon cancer - Chronic activation of the immune system can promote cancer growth, angiogenesis, and cancer progression.

Distant metastasis

- The vast majority of cancer cells do not have the ability to form a metastasis, and simple anatomic arrest of cancer cells in the first tissue they arrive at is not sufficient for them to establish a metastatic lesion. Metastasis requires both an appropriate seed and an appropriately fertile soil. - formation of a metastatic lesion requires a cancer cell to: detach and migrate from its primary location AND survive a passage through the body AND successfully attach, invade, multiply and stimulate angiogenesis in the new location.

Nomenclature of Tumors

- Tumors are generally named after the tissue they are located in - suffix "oma" usually indicates benign tumor - Carcinoma is malignant tumor of epithelial origin - Sarcoma is malignant tumor from transformed cells of mesenchymal origin - Leukemias and Lymphomas are malignant tumors or hemotopoietic cells.

Tumor Cell markers

- substances associated with tumor cells. either produced by tumor cells or produced by the host in response to tumor cells. - markers found on tumor membranes, in blood, in CFS and in urine - some markers are released into the circulatin while others must be identified through biopsy. - markers can be used to:

Anaplasia

- the absence of differentiation and is recognized by a loss of organization and a marked increase in nuclear size with evidence on ongoing proliferation. - In contrast to normal cells that are uniform in size and shape, anaplastic cells are pleomorphic (variable in size and shape). - The most malignant tumors tend to exhibit the most significant degree of anaplasia.

Environmental exposure

- the idea that exposure to environmental agents can increase an individual's risk of cancer is suported by 2 things - environmental agents have been identified that can cause cancer - populations with different life-styles have different types of cancer prevalent.

Initiation

- the initiating event is a genetic mutation that activates protoncogenes or inactivates tumor suppressor gene. - Single somatic cell undergoes a non-lethal but heritable mutation.

Low-grade Intraepithelial neoplasia (dysplasia)

- the most superficial cells still show signs of differentiation, but this is incomplete and proliferating cells are seen far above the basal layer. - normally only the basal cells proliferate.

Transformation

- the process by which a normal cultured cell becomes a cancer cell. - Treatment of normal cultured cells with chemical carcinogens, irradiation and certain viruses can alter their morphology and growth properties. - transformed cells can produce tumors when injected into animals. - Such cells are said to have undergone malignant transformation and exhibit properties in vitro similar to those of cancer cells. - b/c of the similar properties of cancer cells and transformed cells, the process of malignant transformation is being studied extensively as a model of cancer induction.

Three major categories of growth regulatory gene

- these are considered to be critical cancer genes because dysfunction of these genes is a factor in most forms of cancer. - Proto-oncogenes - Tumor suppressor genes - Stability genes (or caretaker genes)

Invasive carcinoma (malignancy)

- this stage begins when the cells cross the basal lamina and begin to invade the underlying connective tissue. - several years my elapse from the first signs of dysplasia to the onset of full-blown malignant cancer.

4 stages of tumors

- tumor staging may be used to determine the msot appropriate therapy, with more aggressive therapy delivered to more invasive disease. Stage I - cancer is confined to the organ of origin Stage II - cancer is locally invasive Stage III - cancer has spread to regional structures such as lymph nodes Stage IV - cancer has spread to distant sites

International TNM system

- used extensively as a general frameworkfor staging tumors where T = extent of tumor size N = node involvement M = presence of distant metastasis prognosis for cure decreases with: increased tumor size, lymph node involvement and metastasis

4 FUNDAMENTAL features that distinguish benign and malignant tumors

1 - differentiation & anaplasia 2 - rate of growth 3 - local invasion 4 - metastasis

6 general characteristics of malignant tumors

Histology - Anaplastic, with abnormal cell size and shape, many mitoses Growth Rate - Rapid Localization/metastasis - infiltrative/frequent metastases Tumor necrosis - Common Recurrence - Common Prognosis - Poor if untreated

6 general characteristics of benign tumors

Histology - Typical of tissue of organ, few mitoses Growth Rate - slow Localization/metastasis - strictly local, often encapsulated/no metastasis Tumor necrosis - Rare Recurrence - rare Prognosis - Good

Cancer as a disease

disease of abnormal growth, division and cell differentiation. Caner refers specifically to a malignant tumor

Primary causes of cancer death (3)

infection hemorrhage organ failure