Chapter 9

2. Metastasis to a Distant Site 5. Entry -Once in the capillary (_____) bed of the target organ, the tumor cells: -______ -then _____ -then ____

-(vascular) -exit the capillary by actively invading the blood vessel's wall -move into the interstitial space -grow in the local tissue

1. Autonomy -Autonomy leads to ____ and ____ Dysplasia: 1. _______ -increase in _____ (____) -increase in ____(____) 2. _____ 3. _______ -classified as ____,____ or ____ or as "______" vs"_____" -often leads to ______ Neoplasia: ______

-Dysplasia and neoplasia 1. Local increase in cells due to rapid proliferation -mitotic activity (Cell division) -mutations (abnormal chromosomes) 2. Variation of cell shape and size: due to rapid mitosis 3. Loss of normal arrangement of cells: disordered cells -mild, moderate, or severe or as "low grade" vs. "high grade" -neoplasia the stage when cancer cells invade and destroy neighboring tissue

1. Local spread 2. Decreased cell to cell adhesions -Cancer cells do not _____ -Thus, cancer cells ___, resulting in _______ -Reasons fro decreased adhesions: (2)

-adhere to other cells like normal cells do -slip between normal cells, invasion of distant tissue 1. changes to the cytoskeleton (protein filaments) 2. Changes to fibronectin (an anchoring molecule): defective, low levels, or loss of fibronectin

1. Autonomy 3. Anchoring junctions -Normal cells are _____ and to the ____ by _____ -The extracellular matrix (basement membrane) is a ______ -Normal cells do not _____ unless they are ____ -Cancer cells display ______, meaning they ______

-anchored to neighboring cells, extracellular matrix, anchoring junctions -meshwork of large organic molecules that bind cells together to make a tissue -divide, anchored -anchorage independence, continue to divide without being anchored

Immunobiology of cancer -Our bodies are equipped to ____ -both ____ and _____ as well as ____ are employed against cancer -The tumor immune surveillance theory is based on the following assumptions (2) -In reality, only some cancers express _____ while other cancers do not

-fight cancer -humoral and cell-mediated immunity, natural killer (NK) cells 1. Cancer cells are constantly arising in normal humans and animals -cell-mediated cytotoxicity evolved because the immune system, needed to detect and destroy cancer cells 2. For the immune system to recognize and reject tumors, cancer cells must express non-self antigens -tumor-specific antigens on their plasma membrane

1. Increased motility -The pseudopodia also enable cancer cells to _____ and allows them to ____ -This increased cell motility is essential for _____ -after detaching from the original tissue, cancer cells use their pseudopodia to _____ or ____ (___ and ____) -Locomotion is integral to the _____

-move, migrate to other parts of the body -invasion -infiltrate adjacent tissue or migrate to the circulation (blood and lymph vessels) -entire process of metastasis

1. Local spread 1. Cellular multiplication -depends on the _______ -is related to _____

-rate of cell division and cell loss -autonomy

Immunobiology of Cancer -When a tumor expresses tumor-specific antigens (TAA), the immune system can _______: -______, _____, and ____ -_____ -_____ -_____

-reject it by employing components of both immunity and inflammation -Cytotoxic T cells, T helper cells, NK cells -Antibodies (B-cells) -Macrophages -Complement proteins

1. Local spread -The mechanisms of local invasion include: (5)

1. Cellular multiplication 2. Decreased cell to cell adhesions 3. Release of lytic enzymes 4. Mechanical pressure 5. Increased motility of the individual tumor cells

2. Cell to cell adhesions Fibronectin= ____: (3) -In cancer cells, fibronectin is ____,____, or ____ causing changes in: (3)

a glycoprotein preset on the cell's plasma membrane and serves as an anchoring molecule to: 1. Hold cells in place in the tissue 2. Help to keep the cell's internal organization 3. Hold receptor molecules in certain arrangement -decreased, defective, or broken down 1. cellular organization (decreased) 2. Cell-to-cell adhesion (decreased) 3. Cellular migration (increased)

Cells in the human body are _____ -the goal of the cellular society is ______, not of the ____ -Cellular social control is made of ______ and ____ that control _____ -Growth factors are _______ -Growth factors are ______,they include: (2)

members of a cellular society -survival of the entire organism, individual cell -cellular mechanisms and genes, the birth and death of cells -proteins produced by cells to communicate cell death and birth between cells -biologic signals, "turn on" or "turn off" 1. Growth inducers: substances that promote cell growth 2. Growth suppressors: signals that inhibit cell growth

Carcinogenesis is a _____ and includes (3)

multi-step process of tumor development 1. Autonomy: the loss of the cell's ability to control growth 2. Anaplasia: the loss of the cell's ability to terminally differentiate 3. Metastasis: the cell has to travel to distant tissue and invade and colonize it

1. Autonomy Another explanation involves ___________, which results in _____: 1. _________ which cause: -______ -_______ 2. _____ 3. _____

mutations that decrease communication between cells, increased cell growth: 1. Altered receptors on the plasma membrane of cancer cells -impaired cell to cell recognition -altered cell responsiveness to growth factors (both inducers and suppressors) 2. Altered gap junctions 3. Altered anchoring junctions

2. Metastasis to a Distant Site 2. Penetration -into either ____ or ___ (____ or___) -Penetration into body cavities (____) -implantation or seeding: cancer cells invade through ____ (e.g. ___) and implant to become ____ in ___ Penetration into capillaries: lymph or blood -Tumor cells spread to distant site by penetrating: ____ OR____ -Capillaries are thin-walled vessels, so they do not _____ -Clusters or single cells separate from the ___ and ____ thought the lymph & blood

-body cavities or capillaries (lymph or blood) -(implantation) -serous membranes (peritoneum), distant metastases in abdominal cavity -lymph capillaries OR blood capillaries -offer much mechanical resistance to penetration by tumor cells -primary tumor mass and disseminate

2. Anaplasia 2. Differentiated cells: -Normal (differentiated) cells can develop into tumors by ____ -Transformation is defined as _____ -Transformation is the process of ____ -The mutated genes involve _____

-transformation -the process by which a normal cell becomes a cancer cell -genetic mutation -growth factors

2. Metastasis to a Distant Site Release into blood -Growth of tumors depends on ___ -Tumor implants cannot grow well without _____ -Tumor cells secrete several ____ that cause ___ (____) and result in ____ -Blood vessels within tumors offer a ______

-adequate blood supply -developing new blood vessels to feed them -growth factors, angiogenesis (the formation of new blood vessels), vascularization of the tumor -direct access of tumor cells into the circulation for further metastasis

1. Local Spread 4. Mechanical pressure -Tumor cells make and secrete a protein named ____(___) -AMF causes cancer cells to grow _____ (____) -The pseudopodia applies ______ that forces them along _____, similar to plants ___ -In addition, pressure from the growing mass could ____, leading to _____ and thus reducing the _____ (____)

-autocrine motility factor (AMF) -pseudopodia (fingerlike projections) -pressure, forces them along the lines of least resistance of a tissue, forcing roots into the soil -block local blood supply, local tissue death, mechanical resistance of the normal tissue (decreased anatomical barriers)

2. Metastasis to a Distant Site Release into lymph: -Initially, the regional lymph nodes may exert a ____, temporarily preventing _____ due to ____ and/or ____ -When a cancer cell becomes lodged in a lymph node, one of the following 4 may occur:

-barrier effect, tumor spread, macrophages and/or NK cell activity 1. Tumor cell death due to inflammatory reaction and macrophage and/or NK cell activity in the node 2. Growth into a discernible lump 3. Sustained dormancy for unknown reasons 4. Detachment from the node and entrance into the larger lymph vessels

Tumor Classification 3. Cell type Tumors are named according to the tissues from which they arise with the suffix "oma" -Epithelial tissue: ____ -Connective and muscle tissue: ____ - Lymphatic tissue: ____ -Glial cells of the CNS: ___ -Bone marrow (blood forming tissue): ___ -involve abnormal growth of ____ that infiltrate and replace ____ and ____

-carcinomas -sarcomas -lymphomas -gliomas -leukemias -blood-forming cells,normal bone marrow and lymphatic tissue

2. Metastasis to a Distant Site 1. Direct or continuous extension -The earliest invasion is ______ -the tumor cells extend into the _____, without _____ -Then the loss of ____ allows the tumor cells to _____

-continuous extension -surrounding tissue as they grow, breaking away from the primary mass -adhesions, slip past one another

1. Autonomy -One mechanism that can trigger normal cells to divide is _____ -When damage occurs, and repair is needed, _______ are triggered to ____ and undergo _____ -______ are secreted by the damaged cells, signaling neighboring cells to _____ and _____ -When the repair is complete, ______

-damage to tissue -non-dividing cells, divide, differentiation -Growth inducers, divide and differentiate -growth suppressors turn off there proliferating cells

1. Autonomy Loss of Growth Inhibition -Normal cells show a ______ growth inhibition (in a culture dish) -Usually once they form a _____, they stop dividing -Cancer cells, continue to _______ forming a _____

-density-dependent -monolayer -grow and pile up on top of each other, multilayer

1. Local Spread 3. Release of lytic enzymes -Tumor cells please lytic enzymes that _______ and ____ -Proteases: ______ -Collagenase: ____ -Plasmin: _____(___) -In normal cells, plasmin is ____ (____) -in cancer cells, plasmin is ____, causing the ____

-digest proteins and destroy normal tissue -destroy proteins in general -destroys collagen -destroys the basement membrane (extracellular matrix) -not activated (plasminogen) -activated, degradation of basement membrane during tumor cell invasion

1. Local spread -Local spread (local invasion) is the ______ and a ____ -At first, local invasion occurs as a ____ -Eventually, ___ or ____ ________ and ______

-first step in metastases and a prerequisite of metastasis -direct tumor extension -cells or clumps of cells detach from the primary tumor and invade the surrounding interstitial spaces

Tumor Classification 1. The degree of differentiation -It ranges from ___ to ____ -It is the _____ -As malignant cells grow and divide, they often lose their _____ so they no longer ____

-grade I to Grade IV -grade I: well differentiated -grade II: moderately differentiated -grade III: poorly differentiated -grade IV: very poorly differentiated -gauge for the degree of malignancy -mature characteristics, resemble their tissue of origin

2. Anaplasia Differentiation -Within a developing embryo, cells are _____ -Undifferentiated cells in adults are known as _____ (____) -they are mostly found in _____ -they are most commonly ______ (develop in to ____ or ____)

-less differentiated -stem cells (precursor cells) -bone marrow -hematopoietic stem cells (RBC or WBC)

2. Anaplasia -Cancerous cells are ____ and resemble ____ -In adults, two types of cells can develop into tumors: (2)

-less differentiated, embryonic cells 1. Stem cells (undifferentiated cells) 2. Normal, differentiated cells

2. Metastasis to a Distant Site 3. Release into lymph or blood: -The most common route for distant metastases is through the ____ because ______ -Tumor cells enter _____ and are carried to the _____ -The first evidence of spread for many types of cancer is a _____ -enlarged axillary lymph node may signal _____ -enlarged groin lymph node may signal ____,____, or ____

-lymphatics, lymph capillaries are the easiest to penetrate (have the thinnest walls) -lymphatic channels, regional lymph nodes -mass in the regional lymph nodes -breast cancer -ovarian, uterine, or prostate cancer

Distinguish between: -Oncogenes= ______ -Proto-oncogenes= ____

-mutated genes that stimulate growth (Cause proliferation) -genes that are normal turned off in a differentiated cell, but when reactivated, they transform a normal cell into a less differentiated cell (cause anaplasia)

1. Autonomy -Dividing cells are more prone to ______ -Cancer is caused by _____ Three main genetic mechanisms have a role in the development of tumors (3)

-mutations -mutation of the genes that regulate cell proliferation and differentiation 1.Mutations resulting in hyperactivity of genes that stimulate growth (oncogenes) 2.Mutations resulting in loss of activity of genes that inhibit growth (inactivated tumor suppressor genes) 3. Over-expression of genes that prevent apoptosis (normal cell death), allowing continued growth

2. Cell to cell adhesions Changes to the cytoskeleton: -The cytoskeleton is composed of a ______ -The protein filaments control the ____ and ____ -In cancer cells, the filaments are _____ resulting in a ____ -round cells ____

-network of protein filaments (microfilaments and microtubules) -shape and internal organization of the cell -not well organized, rounded appearance -slip between cells more easily

2. Anaplasia 1. Stem cells -To produce a growing tumor, a stem cell fails to ______, thus ______ and causing _____

-produce one non-stem-cell daughter in each division, proliferating, imbalance in cell production versus cell destruction

2. Anaplasia Transformation -During differentiation, certain genes, which are called _____, are normally _____ -Re-activation of these genes can transform a _____ to a ___ -Carcinogenic agents can _____ these photo-oncogenes by ______ and thus causing the cell to _____ -Cancer is considered to be a disorder of not only _____ but also of ____ because it _____ -The less the tumor resembles normal tissue, the more ____ (____) and the more _____ it is

-proto-oncogenes, turned off -well-differentiated cell, less differentiated cell -mutate, re-activating them, become less differentiated -cell growth, cell differentiation, resembles undifferentiated tissue -undifferentiated (anaplastic), malignant

1. Autonomy -Cells that disobey the ______ proliferate to form _____ -Cells are genetically programmed to ____,___,______ (____), and ____ -When a cell loses its ability to respond to social control signals (growth factors), it does not _____, rather it ____ -The descendants of this cell become the ______

-social control mechanisms of normal cells; tumors -develop, grow, differentiate (mature), and die -differentiate, continuous to divide without restraint -founders of the neoplasm

Tumor Classification 2. Tissue of origin Invasive tumors: -some tumors retain _____ so that the ______ -some tumors are so ___ that the tissue of origin ____ Carcinoma in situ: -Pre-invasive epithelial tumors (of ____ or ____ origin) that haven't _____ 1. Squamous cell origin: ___,___,___,___,____ 2. Glandular origin: ___,___,___,____,____,___ The time that such lesions remain in site before becoming invasive is ____ (some may take ____)

-some normal function, tissue of origin can be identified -disorganized, cannot be identified (squamous or glandular cell organ) broken through the basement membranes of the epithelium 1. cervix, skin, oral cavity, esophagus, bronchus 2. stomach, endometrium, great, ovary, prostate, bowel unknown (some may take several years)

1. Autonomy How do oncogenes or inactivated tumor suppressor genes cause a tumors cell to proliferate indefinitely? -One explanation, which is just one part of the answer, involves the enzyme _____, which acts on the _____ -A telomere is a ______ -The telomere _______ -When the telomere loses a certain amount of its length, _____ -in immortal cancer cells, the enzyme telomerase _______ -With a full-length telomere, _____

-telomerase, telomeres -repetitive nucleotide sequence of DNA which is present at the end of each chromosome -shrinks each time the cell divides -the cell dies -adds nucleotides back to the telomere -cells continue to divide and do not die

2. Anaplasia 1. Stem cells: -Are not _____ -can _____ -However, normal each division generates _____ and on e_____

-terminally differentiated -divide without limits -one daughter stem cell, differentiated daughter cell

2. Metastasis to a distant site Release into lymph -Tumor spread through the lymphatic system eventually moves into _____ -Tumor cells in lymph vessels form a ____ (____) -The emboss travels to the ____ (___or_____) and from there it moves into the ____ (_____) and enters the ____ &_____ -The first organ's capillary bed that the embolus goes to is in the ____

-the blood -moving mass (embolus) -larges lymph vessels (thoracic duct or right lymphatic duct), venous blood (subclavian veins), right atrium & ventricle -lungs

3. Metastasis Metastasis is: -________ -the major ______ -Primary tumors are more easily eradicated by ____ than trying to control _____ -Often, the primary tumor is not _____ (____) -Still around 50% of malignant tumors are cured by _____

-the spread of tumor cells from the primary site of origin to a distant site -cause of illness and death from cancer -therapies, metastasis -diagnosed before the secondary spread occurs (multiple metastases that are too small to be detected) -current therapies

Tumor Classification 1. The degree of differentiation a. Grade I: well differentiated -closely resemble _____, and thus retains ____ b. Grade II: moderately differentiated -less ____ -more variation in ____ and ___ -increased ____ c. Grade III: poorly differentiated -Does not _____ -much ______ -greatly _____ d. Grade IV: very poorly differentiated -no ____ -great____ -extremely ____

-tissue of origin, some specialized functions -resemblance to tissue of origin -in size and shape of tumor cells -mitosis -not closely resemble tissue of origin -variation in size and shape of tumor cells -increased mitosis -resemblance to tissue of origin -varaiation in size and shape of tumor cells -increased mitosis

2. Metastasis to a Distant Site The 3 step theory of tumor cell invasion of the extracellular matrix: (3)

1. Attachment: surface receptors on the tumor cell bind to the basement membrane in the extracellular matrix 2. Dissolution: the extracellular matrix is degraded by lytic enzymes secreted by the tumor cell (proteases, plasmin) 3. Locomotion: the tumor cell migrates through the degraded basement membrane -the pseudopodia of cancer cells cross the basement membrane enabling the cell to move in and out of blood and lymph vessels

2. Metastasis to a Distant Site 5. Entry Patterns of metastasis are regulated by: 1. _______ -many types of cancer invade ____ 2. ____: -some types of cancer prefer ______ due to ____ and/or ____

1. Blood flow and location of capillary beds -the first capillary bed they encounter 2. Organ tropism -certain target organs, chemotactic factors, specific local growth factors

Different names describing the same condition (5)

1. Cancer 2. tumor 3. Neoplasia 4. Malignancy 5. Carcinogenesis

Cancer is a disease of: (2) Thus, two major properties of cancer cells are: (2)

1. Cell proliferation: increased cell growth and division 2. Cell differentiation: loss of cell differentiation (specialization, maturation) 1. Autonomy: the cell's independence from normal cellular controls which control cell growth and death 2. anaplasia: the loss of differentiation

Cancer Cell Characteristicss Other characteristics of cancer cells 1. _____ -The nuclei of cancer cells are often ____ and _____(____) because _____ -_____ (___,___,____,____) are frequent 2. _____ -Some cancer cells exhibit ____ due to ______ -they engage in ____ even when ___ -However, this is not a good way to diagnose cancer because: (2) 3. _____ -some but not all tumor cells produce ____

1. Changes in nucleus -enlarged and variable in shape (not round), the cell is constantly dividing -chromosome abnormalities (deletions, breaks, inversions, translocations) 2. Metabolic demand -greater metabolic demands, increased rate of cellular division -anaerobic glycolysis, oxygen is present 1 Many neoplasms have normal glycolytic rate 2 many normal tissues exhibit high glycolytic rate (muscles) 3. Tumor cell markers -markers

2. Metastasis to a Distant Site Metastasis involves a series of sequential steps (5) *These steps are not ____ and can _____

1. Direct or continuous extension of local invasion of tumor cells into the surrounding tissue 2. Penetration into: -the body cavities (implantation) -lymphatics of blood capillaries 3. Release into: -lymph -blood 4. Transport to secondary site 5. Entry into the secondary site (metastasis) *mutually exclusive, happen simultaneously

2. Metastasis to a Distant Site 3. Transport to secondary sites -In order to spread to distant organs from the blood (emboli) tumor cells have to: (2)

1. Escape host defenses 2. Lodge in a capillary bed of the target organ

Cells in the body undergo one of three processes, they either (3) -In adults, the rate of cell birth and cell death is ____ in order to ____ -Cell birth = ____(____) -Cell death = ____

1. Grow and divide 2. Differentiate (mature) or 3. Die -kept in balance, maintain organ& tissue mass -mitosis (proliferation) -apoptosis

1. Autonomy Growth factors: -In normal cells (3) -In cancer cells: growth factors are ______: (3)

1. Help regulate cell population density 2. Include inducers and inhibitors (suppressors) 3. Normal cells depend on other cells for growth inducers -unbalanced 1. Cells are chronically stimulated by growth inducers 2. Cells do not respond to growth suppressors 3. Cancer cells either need no growth inducers to divide, or produce their own (autocrine) growth factors

Immunobiology of Cancer Evidence to support the tumor immune surveillance theory: 1. ________ (such as persons with ____,_____, and _____ patients) show ____ including: -_____,____,_____,____,___ and _____ 2. In the serum of some cancer patients, there are _____ and ____ -In addition to ___ and _____ (antibodies), also ____ and ____ are employed against cancer

1. Immune-suppressed individuals (AIDS, organ transplant recipients, and chemotherapy) certain types of cancer -lymphomas, leukemias, skin, uterine, stomach and bladder cancers 2. tumor-reactive antibodies and tumor specific cytotoxic T cells (Tc) -T-cells and B-cells, macrophages and NK cells

Tumor cell markers can be found: (2) -Not all tumor cells produce ___, and thus not all tumors can be _____/____ utilizing lab tests Tumor cell markers are used to (3)

1. On plasma membranes of tumor cells 2. In various body fluids such as blood, cerebrospinal fluid (CSF) and urine -markers, identified/diagnosed 1. Screen and identify individuals at high risk for cancer 2. Help diagnose the specific type of tumor 3. Follow the clinical course of cancer

Metastasis: Tumor Spread Tumor spread depends on: (4) Tumor spread includes: 1. ________ 2. _______ - _______ OR ______

1. Rate of growth of the tumor 2. The degree of differentiation of the tumor 3. The presence or absence of anatomic barriers (mechanical resistance) 4. Other biological factors (health & immune status) 1. local spread by direct invasion of contiguous organs 2. Metastasis to distant sites (organs) -metastasis via lymphatic and blood vessels OR metastasis by implantation (in the abdominal cavity)

Tumors are classified according to: (4)

1. The degree of differentiation 2. Tissue of origin 3. Cell type 4. Whether benign or malignant

Cancer= diseases in which _____ -Derived from Greek word for ______, _____ -Tumor is also referred to as a ______ meaning _____

abnormal cells divide without control and are able to invade other tissues -crab, karkinoma -neoplasm, new growth

Example: cervical cancer Dysplasia: _________ (______) Neoplasia: _____

abnormal changes in size, shape, and organization of mature cells (atypical hyperplasia) invasion of neighboring healthy tissue

1. Autonomy 2. Gap junctions are: _____ -Many carcinogens _____, causing a _______which may play a role in _____

channels connecting adjacent cells that allow small molecules to pass between them, allowing communication and cooperation between neighboring cells -block gap junctions, decrease in intercellular communication, cancer development

Tumor Cell Markers Examples: 1. Antigens: ______ 2. Increased hormone levels, such as insulin in the blood may indicate either: 1. ______ (_____) of a certain ______ (___) OR 2. _____: ____

receptors on the plasma membrane of cancer cells are modified, resulting in being identified by the immune system as foreign antigens 1. Adenoma (adeno-carcinoma), endocrine gland (islet-cell tumor) 2. Ectopic hormonal production: a certain type of lung cancer cells produce insulin

Tumor cell markers are _____ Tumor cell markers may include (5)

substances that are either produced by cancer cells or as the body's response to cancer cells 1. Genes (oncogenes) 2. Antigens 3. Antibodies 4. Enzymes 5. Elevated normal substances such as certain hormones (insulin, prolactin) or calcium

Cell differentiation (maturation) is ____ -As a cell becomes more differentiated it _____

the process by which cells develop specialized organization, structure, and function of the tissue that they constitute by expressing specific genes -decreases or loses its ability to replicate