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Altered Cellular Proliferation and Differentiation

Chapter Introduction

-Second leading cause of death in the US (CVD #1)
-1 in 4 deaths related to cancer

MODULE 1: THE IMPACT OF CANCER ON THE CELL

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Intro

-Cellular proliferation: generation of new daughter cells divided from progenitor (parent) cells. Occurs through meiosis (sperm and ovum) or through mitosis (all other non-germ cells). Cellular proliferation through mitosis occurs continuously and/or in response to needs.
-Differentiation: the orderly process of cellular maturation to achieve a specific function.
-Stem cells: highly undifferentiated units that have the potential to divide into progenitor cells, then daughter cells, which can then mature into more differentiated units with a specific function.

Why is needed, in this case, to achieve homeostasis?

A balance of differentiated cells and undifferentiated cells is necessary to respond to the needs of the body. In the case of cancer, we are concerned with the loss of regulated balance of cell division resulting in the overproliferation and crowding of cells.

Altered Cellular Proliferation and Differentiation

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How does cancer occur at the cellular level?

Occurs because of an unrepaired gene malfunction. More specifically, it is caused by altering those genes that control cell reproduction, growth, differentiation, and/or death. The cell is therefore allowed to grow uncontrollably (altered proliferation). The cell also loses its ability to carry out its specified function (altered differentiation) and does not die when expected.

What is the definition of cancer?

Highly invasive and destructive neoplasms; groups of cells that do not respond to orderly expected patterns of cellular proliferation and differentiation.

CARCINOGENESIS

-Describes the origin and development of cancerous neoplasms (irreversible deviant cellular developments).
-Can emerge from proliferating parenchymal (functional tissue and organ) or stromal (supportive structure) cells, and is manifested from genetic mutations after birth.
-Cancers often related to harmful environmental exposures, which injure the cell DNA and alter the proliferation and differentiation of cells.

What types of cells are highly prone to the development of neoplasms?

Rapidly dividing labile cells, such as epithelial cells and blood cells. Permanent (undividing) cells, such are cardiac myocytes, mature neurons, and the lens of the eye, are not.

What does it mean when cancer "runs in the family?"

Some cancers have a strong familial predisposition. May indicate the presence of a polymorphism (occurrence in more than one form). This means that in families that develop certain types of cancer, this occurs through numerous mechanisms, such as altering the metabolism of agents that predispose to that cancer, deterring the breakdown on carcinogens, altering DNA repair, or impairing cell proliferation.

Role of Genes

-Cancer thought to originate from a single mutated cell (monoclonal origin). Most are spontaneous alterations without an obvious cause. Many mutations are of no consequence, unless they affect genes that regulate cell growth and stability.

What are the three major categories of genes and how are they significant to one another?

1. Mutator genes: genes that repair mutated DNA and protect the genome.
2. Oncogenes: genes that code for proteins involved in cell growth or regulation.
3. Tumor suppressor genes: genes that prohibit overproliferation and regulate apoptosis

Typically, a combination of mutations involving more than one gene category is needed for neoplasms to develop.

Mutator Genes

-Highly effective with a large number of mutations in mutator genes needed to produce cancerous neoplasms.
-If mutator genes are disabled, the environment becomes conducive to neoplastic development as mutations go unrepaired and the cell becomes unstable.

Oncogenes

-"Cancer gene"
-Promote unregulated cell growth and development and can also inhibit cell death.
-Activation of oncogenes is seen in the spontaneous mutation of somatic cells.

What are protooncogenes and why are they important?

-Conversion from a normal gene to one that induces neoplasia depends on the mutation of protooncogenes.
-"Normal" genes in the body with a vital role in regulating cell function; also considered precursor genes that, when activated, become oncogenes through one of three ways:
1. Point mutation (damages a single nucleotide base pair)
--Can arise spontaneously or from exposure to environmental influences
2. Translocation (chromosome breaks, relocates, and unites with another chromosome)
--Ex: leukemias, lymphomas, and many solid tumors
3. Gene amplification (accelerating the replication of genes)
--Ex: Solid tumors such as breast cancer and neuroblastoma

What are the basic mechanisms of action with each type of oncogene transformation?

1. Encoding growth factors to stimulate cell overproliferation
2. Disturbing cell surface receptors and restricting cell-to-cell communication
3. Encoding proteins in the cell nucleus to alter the cell cycle, restrict apoptosis, and impact differentiation of the cell

Tumor Supressor Genes

-Regulate the rate at which cells divide and die so that the optimal number of cells is maintained for homeostasis.
-When inactivated, cells become "immortal," most likely through the alteration of the cell mitochondria. Cell undergoes unrestricted proliferation, and neoplastic transformations are supported.
-Think of them as a wall or a gate: when intact, growth is restricted. A mutation is like a large hole in the gate, allowing unrestricted growth of the cell.

What are the three common tumor suppressor genes that allow neoplasias to form when mutated?

1. p53 gene: most common mutation that leads to development of cancer; located on chromosome 17 and is responsible for opposing cell division in response to cell DNA damage by delaying cell development. This delay allows time for DNA to be repaired. Without p53, cells are unresponsive to the need for repair (cells with damaged DNA are able to reproduce and can become neoplastic).
2. Rb gene: tumor suppressor gene that, when mutated, can result in a rare childhood cancer of the retina
3. BCL-2: inhibits apoptosis. When permanently activated, the cell with the altered gene ignores all of the normal triggers to die and becomes immortal. Cell continues to divide by mitosis, passing along the altered gene to progeny cells. These cells accumulate to form neoplasms.

Carcinogens

A known cancer causing agent; they interfere with molecular pathways and can initiate or promote tumors to form in the body
-Direct: cause modification of cell DNA and interfere with cell function
-Indirect: induce immunosuppression or chronic inflammation, or act in conjunction with other carcinogens to induce DNA damage

Carcinogens: Radiation

-Cause and treatment
-Induces injury by producing reactive oxygen species that damage the cell membrane, allowing the radiation energy to interrupt cell DNA and invoke mutations.
-Labile cells most affected by radiation exposure. When used as treatment however, radiation is aimed at directly killing cells that are highly proliferative- most notably, cancer cells.
-Sun exposure is considered a type of radiation and is mainly attributed to the development of skin cancers.

Carcinogens: Hormones

-Cause and treatment
-Some tumor cells (breast, uterus, prostate, and adrenal glands) are responsive to, or dependent on, hormones for growth.
-As treatment, they can block the effects of tumor growth. Ex: Prednisone (adrenal corticosteroid) can directly kill tumor cells, especially lymph cells, and can inhibit mitosis. Estrogen and testosterone can be manipulated to "starve" the tumor and prohibit further growth.

Carcinogens: Chemicals

-Ex: Tobacco, asbestos, benzene, insecticides, and formaldehyde
-Lead to cancer directly with activation.
-Lead to cancer indirectly. Metabolic conversion is required to initiate or promote cancer development. Enzymes in the body cause the chemical to react with DNA to initiate a carcinogenic response. Genetic and environmental factors influence the activity of these enzymes.
-The basic mechanism for direct or indirect chemical carcinogenesis include the development of highly reactive species, such as free radicals, that induce cell mutation or alter cell proteins or enzymes to interfere with cell regulation.

Carcinogens: Tabacco

-Approx. 1 in 3 cancer deaths can be linked to tobacco.
-Inhalation of smoke is toxic to respiratory mucosa and is known to cause lung cancer.
-Can promote laryngeal, lip, esophageal, and bladder cancer.
-Exhibits a dose effect: the longer and heavier the smoking or tobacco use/exposure, the greater the risk for the development of neoplasms.

Carcinogens: Microbes

-Viruses such as HPV and the hepatitis viruses can lead to cervical cancer and hepatocellular cancer, respectively.
-In process of carcinogenesis, viral proteins are necessary to initiate, maintain, or enhance the malignant phenotype.
-Ex: H. pylori causes chronic inflammation, a common complication of chronic infection which is known to support tumor growth.

What is the initiation-promotion-progression theory?

Proposes that an initiating event must be combined with a promoting event for a cancer to develop and then progress. This theory underscores the idea of cofactors in cancer etiology. If either the initiating or promoting event occurs in isolation, or if the promoter event occurs before the initiator, cancer does not develop.
-Initiating event: causes mutation in cell.
-Promoting event: expansion of the mutated cell's growth and reproduction. The continued growth of the cell depends on continued exposure to the promoter (i.e. chronic inflammation).
-Progression: an extension of the promotion phase with one exception- now the cancerous growth is no longer dependent on continued exposure to the promoter and growth now becomes autonomous.

MODULE 2: THE IMPACT OF CANCER ON TISSUES, ORGANS, AND ORGAN SYSTEMS

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What are the two main characteristics of neoplasms?

1. Autonomy: the unregulated proliferation of the neoplasm
2. Anaplasia: the loss of cell differentiation and therefore the loss of cell function. The greater the degree of anaplasia, the more aggressive (malignant) the tumor will be. Under the microscope: wide variation in size and shape with enlarged nuclei and rapid, atypical mitosis.

What other characteristics do neoplasms exhibit?

1. Loss of cell-to-cell communication, which allows further unrestricted growth of tumor cells.
2. Increased energy expenditure, which deprives unaffected cells of nutrients.
3. Increased motility and loss of cohesion/adhesion, which promotes movement to other locations
4. Rapid angiogenesis, which provides extensive blood flow to the tumor cells and deprives surrounding cells of nutrients
5. Substance secretion, which alters the metabolism and degrades neighboring unaffected cells
6. Present foreign antigens on the cancer cell surface, which can trigger an immune response.

Paraneoplastic Syndromes

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What are paraneoplastic syndromes?

-Hormonal, neurologic, hematologic, and chemical disturbances in the body, which are not directly related to invasion by the primary tumor or metastasis.
Ex: Many tumors secrete ectopic (outside the endocrine gland) hormones that can mimic the body's naturally produced hormones, which can then lead to clinical manifestations that resemble those of a hormone excess. Tumors can also cause generalized numbness, weakness, and loss of neurologic function.

Benign Versus Malignant

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How does a benign tumor compare to a malignant tumor?

-Both terms relate to tumor location and appearance related to the tissue of origin (the unaffected tissue surrounding the neoplasm).
-Benign: tumors that remain localized and closely resemble the tissue of origin (they overproliferate but do not demonstrate a significant loss of differentiation). Not always equivalent to harmless.
-Malignant: tumors that are invasive and destructive, proliferate rapidly, spread to other sites (metastasize), and do not resemble the tissue of origin. an promote ischemia and necrosis of tissue because the tumor uses energy and nutrients needed by unaffected tissues.

Cancer Spread

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What is local spread?

-The proliferation of the neoplasm within the tissue of origin.
-Enlargement of tumors within the tissue of organ promotes loss of function and can result in obstruction, hemorrhage, and necrosis.
-Localized tumors have a more favorable prognosis.

What is direct extension?

-Process of tumor cells moving into adjacent tissues and organs by producing an enzyme that degrades adjacent extracellular matrixes.
-Defining characteristic of malignancy.
-Seeding is a form of direct extension in which neoplastic proliferation occurs within peritoneal and pleural cavities surrounding the affected tissue or organ.

What are metastases?

-Occur when neoplasms are spread to distant sites by way of the lymphatics or blood vessels.
-This is the lethal aspect of cancer.

How do tumors metastasize?

1. Break through the basement membrane (if present) and extracellular matrix
2. Gain access to and circulate within the blood vessels or lymph system (easiest)
3. Leave blood vessels or lymph system and adhere to distant tissues
4. Establish new nutrient network at the distant tissues through a process of angiogenesis.

What is tropism?

Term used to describe the affinity of a primary tumor to a specific distant site. Preferred location of a newly settled neoplasm is somewhat predictable. Factors that promote preferential location include:
1. A favorable environment offered by the new tissue or organ
2. Adherence molecule compatibility between the neoplasm and the new tissue or organ
3. The location of the organ in relation to the path of blood flow

Ex: Tumors that originate in the colon are prone to metastasizing in the liver.

Cancer Nomenclature

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The suffix "oma" indicates what in benign tumors?

-Designates benign tumors based on cell or tissue of origin.
Ex: An epithelioma is a benign tumor of the squamous epithelium
-Papilloma: presents with fingerlike projections

Others terms based on cell/tissue origin:

-Adenomas: benign tumors of glandular epithelial origin
-Teratomas: from germ cells
-Osteomas: from bone cels
-Chondromas: from chondrocytes

The suffix "carcinoma" and "sarcoma" indicate what in malignant tumors?

-Carcinoma: malignant epithelial cells
-Sarcoma: malignant connective tissue cells

Ex: An adenocarcinoma is a malignant tumor of glandular epithelial cells. A chondrosarcoma is a malignant tumor of chondrocytes.

What is carcinoma in situ?

-Carcinomes confined to the epithelium that have not yet penetrated the basement membrane. Tumor is often asymptomatic and represents a favorable diagnosis.

Cancer Classifications

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How is a tumor staged?

-Process of classifying the extent or spread of neoplasms and refers to the tumor size, location, lymph node involvement, and spread.
-The higher the number, the more extensive the tumor size and spread.

Tumor size
TX = Primary tumor cannot be evaluated
T0 = No evidence of primary tumor
Tis = Carcinoma in situ
T1, 2, 3, 4 = Size/extent of the primary tumor

Node (lymph) involvement
NX = Regional lymph nodes cannot be eval
N0 = No regional lymph node involvement
N1, 2, 3 = Involvement of regional lymph nodes (# and/or extent of spread)

Metastases
MX = Distant mets cannot be evaluated
M0 = No distant mets
M1 = Distant mets

How is a tumor graded?

-Process of differentiating the level of anaplasia depicted by the tumor.
-As the tumor grade increases, the cells become more deviant from the tissue of origin. Those that are graded lower (I or II) resemble the tissue of origin in terms of size, shape, structure, and mitotic activity. Those with a higher grade (III or IV) demonstrate little resemblance to the tissue of origin.

Cancer Prognosis

-Typically communicated based on a 5-year survival rate (includes those who are cancer free, in remission, or living with cancer).
-Ex: patients diagnosed with stage III or IV ovarian cancer in which tumor could not be completely removed and treatment was suboptimal, the 5-yr survival rate was less than 10%.

General Manifestations

1. Systemic inflammatory/immune response
-Lymphadenopathy, fever, anorexia/cachexia
2. Increased metabolic rate induced by tumors
3. Paraneoplastic syndromes
4. Local effects of tumor encroachment or obstruction on neighboring tissues
-Bleeding, bruising, poor wound healing, pain, loss of function

What is lymphadenopathy?

-Condition of enlarged lymph nodes throughout the body; hyperplasia occurs in response to lymphocyte immunoreactivity, specifically against the developing neoplasm.
-Rapid, acute enlargement of lymph nodes often produces tenderness (in the case of acute infection).
-Low-grade, chronic hyperplasia is nontender.

What is cachexia?

-Unexplained weight loss and tissue wasting
-Can be the result of inflammatory mediators, along with excess energy use by the proliferating neoplastic cells; also result of early feelings of fullness with eating.

Local manifestations are site dependent and are related to-

1. The space occupied by the tumor that impinges on the local structures
2. The loss of function in the tissue or organ that is being "taken over" by the tumor.

What is often the first sign of a tumor?

A palpable mass such as those found in the breast, testicle, and lymph nodes.

Diagnostic Tests

-Imaging studies: allow direct visualization via radiographs, endoscopic examination, ultrasound, CT or MRI scans; useful in determining presence, size, and location of tumors.
-Biopsy and cytology studies: cells can be removed and examined to determine the presence and stage of neoplasms. In most cases, definitive diagnosis can only be made with microscope exam.
-Tumor markers: substances that may be detected in cells or body fluids and can provide clues to the presence, extent, and treatment response of certain neoplasms; can be comprised of hormones, enzymes, and immunoglobulins and may be produced by the tumor itself or unaffected cells in the body in response to the presence of a malignant or benign tumor. Many are expressed as protein antigens.
-Others: decreased Hbg levels may indicate anemia; WBCs, platelets, and RBCs levels may also be increased, particularly after chemotherapy.

Cancer Treatment

Goals:
1. Completely eradicate the neoplasms
2. Control continued growth and spread
3. Reduce symptoms without curing the cancer

What are the major treatment strategies to achieve these goals?

Surgery, chemotherapy, radiation, hormones, and immunotherapy. Also, care of the patient with cancer and their family involves the provision of psychosocial support needed to address the anxiety and depression that may accompany the diagnosis. Palliative care treats the symptoms (pain, fatigue, N&V, pruritis, and diarrhea) without curing the cancer.

Cancer Prevention

Avoid known carcinogens, participate in health promotion activities (exercising moderately and consume a balanced healthy diet), accepting vaccinations when indicated, and taking measures to protect against chronic injury, including exposure to reactive oxygen species.

Children and Cancer

-Leading cause of death by disease in ages 1-14yrs.
-Most childhood cancers originate in the mesodermal germ layer, which develops into bone, blood, blood vessels, muscle, lymphatics, connective tissue, and kidneys.

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