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Angiogenesis

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stimulation of new blood vessel growth More advanced cancers can secrete mutliple factors that make this happen; facilitate feeding the tumor An

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When do cancers need their own blood supply?

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Once they grow larger than 1 millimeter in diameter= in order to deliver oxygen and nutrients to themselves

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Normal blood vessel growth

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limited to areas of wound healing and to uterus during menstrual cycle

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Angiogenic factors

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vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) They work by recruiting new vascular endolthetlial cells and initiating the proliferation of existing blood vessel cells, and allow small cancers to become larger cancers

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Benign vs. malignant tumors

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Benign grows slowly well-defined capsule not invasive well differentiated (has committed to a cell type, looks like the tissue from which it arises) low mitotic index (dividing cells are rare) do not metasastaize Malignant grows rapidly not encapsulated invasive Anaplasia: poorly differentiated (multiple cells it can become; may not be able to tell from what tissue it arose) high mitotic index (many dividing cells) can spread easily (metastasize)

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anaplasia

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loss of cellular differentiation

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Cancer

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malignant tumor

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tumor

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originally referred to any swelling that was caused by inflammation; but now it is reserved to a new growth or neoplasm

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How are cancers named?

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By the cell type they originate from

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Carcinomas

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cancers arising from epithetlial tissue

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Adenocarcinomas

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arise from ductal or gladular structures

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sarcoma

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cancers arising from connective tissue suffix

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lymphomas

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cancers of lympatic tissue

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luekemias

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cancers of blood-forming cells

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Carcinoma in Situ

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CIS; refers to preinvasion epithelial malignant tumors of glandular or squamous cell origin early stage cancers are localized to epitherium and have not broken through basement membrane or invaded surrounding stroma

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Cancer Staging

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critical to establish if the cancer has spread, or what stage it is in. Stage 1: cancer confined to the organ of origin Stage 2: locally invasive Stage 3: cancer that has spread to regional structures (lymph nodes) Stage 4: cancer that has spread to distant sites, like liver cancer to the lungs

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Clinical manifestations of cancer

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pain, fatigue, cachexia, anemia, leukpenia, thrombocytopenia, infection, paraneoplastic syndromes

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How is cancer discovered?

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screening tests, routine exams, after investigation of symptoms

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Symptoms of cancer

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are as diverse as the types of cancer; location of cancer can determine symptoms by physical pressure, obstruction, loss of normal function, or cancer can cause problems far away from the source by pressing on nerves or secreting bioactive compounds Need tumor tissue to be obtained to establish a definite diagnosis and correctly classify the disease

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Pain

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little or no pain during initial stages pain strongly influenced by fear, anxiety, sleep loss, fatigue and overall deterioration Cancer associated pain can arise from a variety of direct and indirect mechanisms (direct pressure, obstruction, invasion of sensitive structure, stretching of visceral surfaces, tissue destruction, tissue infection, inflammation Can be at the site of the primary tumor or distant Certain sites are more prone to cancer-associated pain (bone metastase cause pain due to periosteal irritation)

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Priorities in treating pain

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1. control pain rapidly 2. prevent recurrence of pain

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Fatigue

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symptom of cancer and cancer treatment Causes: sleep disturbances, various biochemical changes secondary to disease/treatment, numerous physiological factors, level of activity, nutritional status, and other environmental factors Also lose portions of muscle function needed to preform nomral physical activitis

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How is fatigue described by patients?

answer

tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, boredom, lack of motivation, decreased mental status

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Cachexia

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constellation of symptoms including anorexia, early satiety (filling), weight loss, anemia, asthenia, taste alterations, altered protein, lipid, and carb metabolism

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Anemia

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due to chronic bleeding (iron deficiency), severe malnutrition, cytotoxic chemotherapy, and malignancy in blood-forming organs Iron is also malabsorbed defects in erythropotein production, shortened red cell survival

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Lekopenia

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direct tumor invasion can cause this to happen, decreased total white blood cell count

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Thrombocytopenia

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decreased number of blood platelets major cause of hemorrhage in people with cancer, treated with platelet transfusions

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Infection

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most significant cause of complications and death in patients with malignant disease when absolute grandulocye count falls below 500 cells per uL, the risk of serious microbiral infeciton increases immunosuppression occurs with underlying cancer and treatment Surgery can lower resistance Hospital acquired infections increase because of indwelling

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paraneoplastic syndromes

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syndromes that cannot be explained by the local or distant stpread of the tumor by the effects of hormones released by the tissue form which teh tumor arose

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Transformation

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the process by which a normal cell becomes a cancer cell

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Autonomy

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refers to the cancer cell's independence form normal cellular controls and is part of the transformational process

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Anchorage independent

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continue to divide even when suspended in a soft agar gel

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immortal

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cancer cells divide for years under appropriate laboratory conditions

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Anaplasia

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absence of differentiation most malignant tumors tend to have he most anaplasia and be the least differentiated

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Pleomorphic

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anaplastic cells of variable size and shape

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Cancer stem cells

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they can divide asymmetrically, and can give rise to another stem cell and one daughter cell that ultimately terminally differentiates into diverse cell types, depending on the need of the tissue Cancers may arise from cancer stem cells only a small subset of cancer cells have the ability to divide indefinitely and give arise to full-blown cancer It is the most important cell in the cancer (tumor initiating cell) Need to kill it to kill the cancer

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Adult stem cells

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have two characteristics: self renew and they are multipotent (have the ability to differentiate into multiple different cells) Regeneration of tissues depend on their regeneration from a small fraction of adult stem cells

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Features of cancer cells

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Anchorage independent (can divide on top of each other) Immortal Anaplasia pleomorphic Cancer cells are independent from normal cellular control = autonomy

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Tumor markers

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substances produced by cancer cells that are found either in or on the tumor cells or in the blood, spinal fluid, or urine can be increased by noncancerous as well as cancerous conditions Include: hormones, enzymes, genes, antigens, and antibodies Ex. Adrenal medulla secretes the catecholamine epinhephrine. Benign tumors also scerete this in excess leading to rapid pulse, high BP, sweats, tremors; high blood or urine levels in someone strogly suggests presence of tumor

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Epigenetics

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DNA chemically modified but not mutated do not involve changes in DNA sequences Gene silencing of key regulatory genes collaborate with the genetic changes and environmental-lifestyle factors to cause the development of cancer epigenetic mechanisms can be modified by lifestyle, particularity diet and environment, pharmacologica interventions, or both Aging affects DNA methylation pattern of epigenome cell types patterns diverged in older twins responsible for tissue-specific gene expression during cellular differentiation

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Gene silencing

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is passed from mother to daughter cells during cell division; does not require mutations or changes in DNA sequences the same DNA sequence can produce dramatically different phentoypes depending on chemical modifications that alter the expression of genes Whole regions of chromosomes can be shut off Changes in gene silencing= lead to cancer silencing can shut off critical tumor suppressor genes in the absence of mutation in the gene = may be a faster way to create cancer cells loss of silence can contribute to inappropriate expression of oncogenes

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3 major areas of epigenetics

answer

1. Methylation (additional of methyl group CH3 to cytosine ring) 2. histone modification (acetylation, alterations i chromatin) 3. Micro-ribonucleic acids (mrRNAs)= target gene expression post-transcriptionally

question

What affects DNA methylationdirectly?

answer

Nutrition because adipose tissue is endocrine tissue, obese individuals accumulation macrophages that secrete various proinflmmatory signaling molecules and cytokines

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Developmental Plasticity

answer

degree to which an organism's development is contingent on its environment sensitivity to envirnmental lifestyle factors influences that mature phenotype and is dependent on the interactions of both genome and epigenome

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DNA methylation

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many cancers have increased methylation of DNA in the promoter region of the tumor suppressor genes abberant methylation can lead to silencing of tumor suppressor genes

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Normal cells becoming cancerous

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Cancer is predominately a disease of aging Clonal proliferation multiple mutations must occur before cancer can develop Epigenetics (modified DNA, but not changed)

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Clonal proliferation or expansion

answer

mutatnt cell has selective advantage over its neighbors ; progeny will then accumulate faster than its nonmutant neighbors

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Risk factors for developing cancer

answer

...

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Epigentics cause cancer?

answer

epigenetic changes coupled with genetic changes and environmental-lifesytle factors cause the development of cancer

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Micro-ribonucleic acids (mrRNAs)=

answer

target gene expression post transcriptionally act on oncogenes or tumor suppressor genes

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Genetic influence on cancer

answer

parental exposure prior to conception In-utero exposure (nutrition, toxins, stressers, lifestyle) Exposure to toxins in breast milk after birth Gene-environmental interactions

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Risk factors for developing cancer

answer

tobacco (multipotent carcinogenic mixutre) (with alcohol=even greater risk, alcohol is a solvent) Diet (Xenobiotics= carcinogen in food) Obesity (free fatty acids and adipose is very metabolically active tissue=contributes to cell damage) Alcohol consumption ionizing radiation ultraviolet radiation (skin) sexual behaviors (HPV, STD, Hep B and C) Electromagnetic fields (are they or are they not carcinogenic) Occupational hazazards Air pollution (outdoor and indoor)= causes inflammatory processes in the lungs Physical activity (inactivity= more prone; gut=express free radicals and stay in the body longer)

question

What are tumor markers used for?

answer

screening, diagnosis, observation

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Oncogenes

answer

mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate (accelerate) proliferation

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Tumor-suppressor gene

answer

encode proteins that in their normal state negatively regulate proliferation; anti-oncogenes

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Proto-oncogene

answer

normal, nonmutant state oncogene ex. Epidergmal growth factor, or growth factor receptor

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Inflammation and cancer

answer

epidemiologic studies strongly support the conclusion that active immune response in chronic inflammation predipsoses to cancer ex. ulcerative colitis for 10 years or more, they have a 30x more chance in the risk of developing colon cancer

question

Why does inflammation lead to cancer?

answer

after injury and during infection, inflammatory cells (neutrophils, lymphocytes, and macrophages) release cytokines, growth factors, and survival factors that stimulate local cell proliferation and new blood vessel growth to promote wound healing by tissue remodeling It causes cellular injury: Cytokine release form inflammatory cells free radicals mutation promotion decreased response to DNA damage

question

point mutations

answer

the alteration of one or of a few nucleotide base pairs This can have a profound effect on the activity of proteins ex. in RAS gene converts it from a regulated pro-oncogene to an unregulated oncogene, an accelerator of cellular proliferation

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Chromosomal translocation

answer

a piece of one chromsome is translocated to another chromosome, can activate oncogenes by way of either two distinct mechanisms 1. can ecause excess and inappropriate production of a proliferation factor 2. can lead to production of novel proteins with growth-promoting properties

question

Gene amplification

answer

turns on oncogenes result of duplication of a small piece of a chromosome over and over again, so that instead of the normal two copies of a gene, tens or even hundreds of copies are present results in increased expression of oncogene, or in some cases drug resistance genes

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tumor suppressor genes

answer

genes whose major function is to negatively regulate cell growth and prevent mutations may normally slow the cell cycle, inhibit proliferation resulting from growth signals, or stop cell division when cells are damaged ex. when RB gene is inactivated, the cell division cycle can proceed unchecked

question

Types of misregulation in cancer

answer

1. alterations in pro-growth and anti-growth signals 2. telmoeres and immortality 3. Angiongenesis

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apoptosis

answer

cells have this mechanism that causes them to self-destruct when growth is excessive and cell cycle check points have been ignored; it is triggered by diverse stimuli like normal development and excessive growth

question

6 pathways that must be misregulated for cancer to develop What gene mutations alter growth signals?

answer

1. cancer cells must have mutations that enable them to proliferate in the absence of external growth signals (autocrine stimulation)= growth factors secreted 2. increase in growth factor receptors 3. signal cascade from the cell surface receptor to the nucleus may be mutated to the on position (signal from cell surface receptor is mutated to on) 4. cells usually receive diverse anti-growth signals from their normal milieu; contact with other cells/basement membranes signal them to stop proliferating; this normal antigrowth signal must be inactivated Inactivation of the Rb tumor suppressor mutation of the ras intracellular signaling protein Activation of protein kinases that drive the cell cycle 5. cells have a mechanism that causes them to self destruct= apoptosis (disabled pathway)= Mutation of the TP53 gene

question

TP53 gene

answer

When this gene is mutated, cells become resistant to apoptosis

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Rb tumor suppressor

answer

Normally inhibits the cell division cycle; when inactivated, the cell division cycle can proceed unchecked (ex. mutated in childhood retinoblastoma and in many lung, breast, and bone cancers)

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RAS intracellular signaling protein

answer

normally inactive, but exchanges GDP for GTP to become active= and then RAS sends growth signals throughout hte cell by interacting with a number of signaling proteins Becomes inactive with GTP is hydrolysis back to GDP Oncogenic RAS has a mutation that blocks this hydrolysis

question

t(8;14 ) translocation

answer

Burkitt lymphomas A chromosome that has a piece of chromosome 8 fused with a piece of chromosome 14 myc-proto-oncogene found on chromosome 8 is normally turned on at low levels in proliferating lymphocyte and is turned off in mature lymphocytes MYC protein is part of the positive signal for proliferation; if accidental formation of the translocation occurs, the myc gene is placed under control of B cell immunoglobulin Ig present on chromosome 14= switched to high levels (direct by Ig promoter)= drives proliferation and blocks differentiated; cancers of maturing B cells

question

caretaker genes

answer

encode for proteins that are involved in repairing damaged DNA

question

How are normal genes mutated?

answer

point mutations chromosome translocation gene amplification mutation of tumor suppressor genes loss of heterozygosity gene silencing

question

Telemoreres

answer

body (somatic cells) are not immortal, can divide only a limited number of time Telemoeres are protective caps on each chromosome cancer cells can restore telomeres

question

Tumor spread

answer

direct invasion of continuous organs (known as local spread) 1. detachment and invasion 2. survival and spread in circulation 3. selective adherence 4. escape from circulation

question

Metastases

answer

movement do distant organs via lymphatics and blood highly inefficient; but as diversity with the cells increase, the number of cells in the cancer mass with new abilities to facilitate metastasis grows most cancer cells cannot successfully cause metastases; they must survive multiple physical and physiologic barriers in order to survive, spread, and proliferate in distant locations and the destination (soil) must be receptive to the growth of cancer

question

Stages of Metastases

answer

Detachment and invasion survival and spread in circulation selective adherence escape from circulation

question

detachment and invasion

answer

must be able to detach from stroma and migrate (normally attached to ECM To facilitate cancer spread= release proteases and protease activators (MMPs) and plasminogen activators Down regulate key mediator of cell detachment (E-cadherin and intergins)

question

Active proteases

answer

digest ECM and basement membrane=pathway for which cells can move

question

three step theory of invasion

answer

1. tumor cell attachment (fibronectin and laminin) 2. degradation of dissolution of matrix (enzymes) 3. locomotion into the matrix (invadopodia

question

Survival and spread

answer

tumor cells have adapted to a hypotoxic environment and are resistant to apoptosis

question

selective adhesion in favorable sites

answer

cells gain access to circulation through new tumor-associated blood vessels or angiongesis Mobile tumor cells are able to enter circulation (leakly newsly made blood vessels) once in circulation, cells must be able to withstand the physiological stress of travel in the blood and lymphatic circulation Sometimes they bind to blood platelets=protect themselves

question

Pattern of Metastasis

answer

dictated by interaction between cancer cells and the microenvironments in which they land Cancer cells spread through vascular and lymphatic tissue; the neovscularization of cancer offers malignant cells direct access to the venous blood =anatomic pathways help determine how colon cancers spread to the liver Selectivity of different cancers for different sites

question

Escape from circulation and development of a new microenvironment

answer

cancer cells can arrive at a new location and survive but not proliferate to form a clinically relevant metastasis if they do not make the transition from simple survival to robust proliferation= dormancy state Help proliferation= normal cells from local bone marrow stem cells are recruited

question

Organ tropism

answer

preferential growth of cancerous cells in certain organs Influenced by: growth factors, chemokines, hormones, tissue-selective homing receptors, and chemotactic factors

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