Chapter 12: Cancer Biology

Inflammation as a Cause for Cancer

*Inflammatory cells release compounds such as reactive oxygen species (ROS) that promote mutations and block the cellular response to DNA damage* ~Susceptible organs Gastrointestinal (GI) tract, pancreas Thyroid gland Prostate, urinary bladder Pleura, skin

Angiogenesis

- The growth of new blood vessels -Advanced CA secrete angiogenic factors to feed

Neoplastic Progression

-"Step-wise" accumulation of alterations occur in specific genes Ex) Colon-small, larger, cancer, mutations increase

Gene Amplification

-A small piece of chromosome is duplicated over and over. -Results in an increased expression of an oncogene. -25% cases of neuroblastoma: *N-nyc oncogene undergoes gene amplification*

Cancer cells produce hormones or hormone-like proteins

-ADH-Syndrome if inappropriate ADH -ACTH-Cushing syndrome -PTH-related protein-Hypercalcemia (confusion) -Cancer cells produce proteins that affect clotting-DVT-Please be alert for patients who present with DVT/PE and no readily identifiable cause -Do they have an occult cancer? Possibly, look!

Inactivation of tumor-suppressor genes

-Allows unregulated cellular growth. -Takes two hits to inactivate the two alleles of a tumor-suppressor gene. e.g. *retinoblastoma RB gene* -*Common cause of inherited mutations that predispose to cancer*

Oncogenes

-Are mutant genes that, in their nonmutant state, direct protein synthesis and cellular growth

Telomeres

-Are protective caps on each chromosome that are held in place by a telomerase. -Telomeres become smaller and smaller with each cell division. -Cancer cells can activate telomerase, leading to continued division.

Benign vs Malignant Tumors

-Benign: Slow growth, well-defined capsule, not invasive, well differentiated, low mitotic index, does not metastasize -Malignant: Rapid growth, Not encapsulated, invasive, poorly differentiated (anaplasia), high mitotic index, can spread distantly (metastasis)

Cancer Metabolism

-CA cells have different nutritional requirements -CA cells perform glycolysis even in the presence of oxygen=rapid cell growth

Pain

-CA that produce pain=gift -Worry more about CA that do not cause pain

Epstein-Barr virus (EBV)

-Can lead to the development of B-cell lymphomas. -B-cell lymphomas can develop in persons who receive an organ transplant: Posttransplant lymphoproliferative disorder (PTLD). -Is associated with Burkitt lymphoma in areas of endemic malaria and with nasopharyngeal carcinoma. -Evidence of chromosomal translocation

Point Mutations (small)

-Changes occur in one or a few nucleotide base pairs. -*Ras gene converts a regulated proto-oncogene to an unregulated oncogene, accelerating growth*. -Found in pancreatic and colorectal cancer. -Direct DNA sequencing can detect these clinically

Bacterial Cause: Helicobacter pylori

-Chronic infections -This bacteria can both directly and indirectly produce genetic and epigenetic changes in infected stomachs. --Mutations in the p53 gene --Alterations in the methylation of specific genes

Oncogene Addition

-Common driver for mutations -CA are addicted to their mutant CA gene -Treat addiction, treat the CA Ex) HER2

Gene Silencing

-Emerging as major cause of cancer -Whole regions of chromosomes are shut off while the same regions in other cells remain active. -Does not require mutations or changes in the deoxyribonucleic acid (DNA) sequence. Can shut off critical tumor-suppressor genes.

Tumor-suppressor genes-The Brakes

-Encode proteins that, in their normal state, negatively regulate proliferation. -Are also referred to as anti-oncogenes.

CA Local Spread

-First step in metastasis -Cancer often spreads first to regional lymph nodes through the lymphatic system and then to distant organs through the bloodstream

Oncologic Emergencies: Pericardial Effusion

-Found on autopsy in 5-10% of CA (lung, breast, leukemia, lymphoma) -Origin may be radiation, drugs, autoimmune disease, infection -Dx: Echocardiogram

Genetics in Cancer-Prone Families

-In rare families, cancer can be inherited in an autosomal dominant fashion as a result of mutations in tumor-suppressor genes. Ex) TP53(important in protection of genome), RB1, and BRCA1

Chronic hepatitis B and C infections

-Increased risk of liver CA -HBV vaccine is expected to decrease the incidence of chronic hepatitis B significantly. -No vaccine for C

Human papillomavirus (HPV)

-Is implicated in cervical cancer. -Is readily detected by the Papanicolaou (Pap) test. -Vaccines protecting against the common oncogenic HPV types (HPV 16 and 18 [types that cause > 70% of cervical cancers] and HPV 6 and 11 [types that cause 90% of genital warts]) have been approved.

Cachexia

-Is the most severe form of malnutrition. -Leads to protein-calorie malnutrition and progressive wasting

Oncologic Emergencies: Superior vena cava syndrome

-Local effects of tumor growth may cause compression of blood vessels -Seen in lung CA and occlusion of vascular catheters

*Anaplasia*

-Microscopic hallmark of cancer cells -loss of cellular differentiation "without form" -Pleomorphic: Variable sizes and shapes -Malignant cells will not retain function-reduced ability

Genetics and CA

-Molecular classification of CA now enhanced by immunohistochemical analysis of protein expression + extensive molecular analysis of tumor +single gene or panel of gene analysis

Fatigue

-Most frequently reported symptom of cancer and cancer treatment -Immune cells such as monocytes and lymphocytes can penetrate BBB where they secrete cytokines and inflammatory mediators. e.g. lead to helplessness and hopelessness in cancers may arise secondary to CNS effects of products released by immune cells

Malignant Tumors

-Named according to the cell type from which they originate Ex) Malignant mammary adenocarcinoma vs fibroadenoma (benign)

Benign Tumors

-Named according to the tissues from which they arise, and include the suffix "-oma" -Ex)Lipoma-fat

Kaposi sarcoma herpesvirus (KSHV)

-Occurs in a significantly more virulent form in individuals who are immunocompromised, especially in those with acquired immunodeficiency syndrome (AIDS).

Chromosome translocation

-Piece on one chromosome is transferred to another. -Personalized medicine -imatinib(targeted chemo) for CML (philadelphia chromosome) -Example Burkitt Lymphoma

Neoplasia

-Process of "new growth" -Neoplasms proliferate to form new tissue

Alterations in Progrowth and Antigrowth Signals

-Secretion of growth factors (autocrine stimulation) *enables tumor to proliferate in the absence of external growth signals*. -Mutation in the Ras *intracellular signaling protein* -Most common mutations conferring resistance to apoptosis occur in the TP53 gene (tumor-suppressor gene)

*Tumor Markers*

-Substances produced by benign or malignant cells -Antigens that are expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor -Helpful during surveillance and diagnosis and following clinical course -Are found on or in a tumor cell, in the blood, in the spinal fluid, or in urine. Hormones Enzymes Genes Antigens Antibodies

Paraneoplastic syndromes

-Symptom complexes are triggered by a cancer but are not caused by direct local effects of the tumor mass. -Are caused by biologic substances released from the tumor (e.g., hormones) or by an immune response triggered by the tumor. -Can be life threatening.

Tumor Marker Flaws

-Testing large populations will always detect a few normal individuals with test results at the high end of normal-false positives -Some individuals with disease will test in normal range-false negative -Non malignant disease may elevate markers

Example of Inflammation induced CA

-Those with ulcerative colitis for 10 years or more have up to a 30-fold increase in developing colon cancer. -The risk of lung cancer among women with chronic asthma (66% increase)

Sentinel Node

-Used to describe the initial lymph node to which the primary tumor drains -Initial metastasis in breast cancer is almost always lymphatic, therefore extent of disease may be determined through lymphatic mapping and sentinel lymph node biopsy -Radioactive tracer and blue dye is injected into tumor to determine the first lymph node in the route of drainage-examined for disease

Hematogenous Spread

-Venous blood from GI tract, pancreas, and spleen is routed through the portal vein to the liver, and all vena cava blood flows to the lungs, -Liver and lungs are the most frequent metastatic sites for hematogenous spread

Cancer Stem Cells

-Very small number of blood forming cells are stem cells -Self-renewing -Multipotent

Carcinoma in situ (CIS)

-preinvasive malignant tumor -*LOCALIZED* and has not broken through the basement membrane or invaded the surrounding stroma -Are NOT malignant

Paraneoplastic Syndrome

-tumor markers have biologic activity -Symptom complexes triggered by a CA

Human Carcinogenesis

1. Activation of proto-oncogenes 2. Mutation of tumor-suppressor genes 3. Mutation of genes allowing for continued tumor growth

A woman who is immunosuppressed has the Epstein-Barr virus. For which cancer should the nurse assess this individual?  1. B-cell lymphoma 2. Kaposi sarcoma 3. Liver cancer 4. Cervical cancer

1. B cell lymphoma. In individuals who are immunosuppressed because of HIV infection or because of drugs given for an organ transplant, persistent EBV infection can lead to the development of B cell lymphomas. 2. HHV8 is linked to the development of Kaposi sarcoma, a cancer that was once seen primarily in older men but now occurs in a markedly more virulent form in immunocompromised individuals, especially those with acquired immunodeficiency syndrome (AIDS). 3. Chronic hepatitis B infections are common in parts of Asia and Sub-Saharan Africa and confer up to a 200-fold increased risk of developing liver cancer. 4. Virtually all cervical cancer is caused by infection with specific types of HPV, which infects basal skin cells and commonly causes warts.

CIS Prognoses

1. Remain stable for a long time 2. Progress to invasive and metastatic cancers 3. Regress and disappear

A nurse hears in report that an individual has benign tumors. What does this mean? The tumors: 1. Are poorly differentiated. 2. Are encapsulated. 3. May develop anaplasia. 4. May spread to a distant location.

2. Are encapsulated. Benign tumors are usually encapsulated and do not invade the capsule that surrounds them. 1. Benign tumors are typically well differentiated; malignant cancer is poorly differentiated. 3. Benign tumors maintain some normal tissue structure; malignant cancer develops anaplasia. 4. Benign tumors do not spread or metastasize to distant locations; malignant cancer metastasizes.

Tumor markers are found: 1. On the surface of organs of the body 2. By examination of serum 3. By radiographic examination 4. By physical examination

2. By examination of serum. Tumor markers are produced by cancer cells and may be released into the blood, where they can be measured. 1. Tumor markers are found on cancer cells or tumors, blood, spinal fluid, or urine not on healthy cells and organs. 3. Tumor markers cannot be visualized by radiographic examination. 4. Tumor markers cannot be identified with physical examination.

Chromosome instability may result in the overexpression of: 1. Tumor-suppressor genes 2. Heterozygosity 3. Oncogenes 4. Point mutations

3. Overexpression of oncogenes. Chromosome instability (often referred to as CIN) also appears to be increased in malignant cells. Chromosome instability results in a high rate of chromosome loss, as well as loss of heterozygosity and chromosome amplification. Each of these events can accelerate the loss of tumor-suppressor genes and the overexpression of oncogenes. 4. A point mutation in the ras gene converts it from a regulated proto-oncogene to an unregulated oncogene, an accelerator of cellular proliferation.

Proto-oncogenes

Are normal nonmutant genes that code for cellular growth.

Hayflick limit

Body cells are not immortal and can only divide a limited number of times

An asymptomatic patient who is worried about developing breast cancer due to the fact that it runs in her family asks the nurse if she could have a mammogram to see if she has any lumps. The nurse informs the patient that a tumor usually is undetectable until it has doubled 30 times and contains more than 1 billion cells. This means that at this point it measures approximately which of the following sizes : a) 5cm b) 4cm c) 1cm d) 3cm

C) 1 cm

*Malignant epithelial tumors*

Carcinomas

Diagnosing and staging

Involves the size of the tumor, the degree to which it has invaded, and the extent of the spread. Stage 1 >>Is confined to its organ of origin. Stage 2 >>Is locally invasive. Stage 3 >>Has advanced to regional structures. Stage 4 >>Has spread to distant sites.

Liver and Germ Cell Tumors

Secrete a protein known as alpha fetoprotein (AFP) into the blood

Staging using WHO TNM System

T1, N0, M0=good chance of survival T3=highly invaded

Cancer-Causing Mutations

~Predominantly a disease of aging ~Clonal proliferation or expansion (vs usual repair/apoptosis of damaged genes) ~Increased growth rate and/or decreased apoptosis (CANCER WINS) ~Multiple mutations are required before cancer can develop (increase as we age)