PathoPhysiology Chapter 7

1. Chapter 7
Neoplasia
1

2. NEOPLASIA
• Means “new growth”
• Implies abnormality of cellular growth/tumor
• Malignant neoplasm is cancer
• Benign growth is generally easily cured
• Malignant cancer may not be survivable
• Cancer is associated with altered expression
of cellular genes
Neoplasia
2

3. BENIGN VS. MALIGNANT GROWTH
Malignant Tumor
• Can kill host if untreated
• Confirmed by invasive or metastasizing
nature
• Tissue-specific differentiation (does not closely
resemble tissue type of origin)
• Greater degree of anaplasia indicates aggressive
malignancy
• Grows rapidly, may initiate tumor vessel
growth, frequently necrotic, dysfunctional
3

4. BENIGN VS. MALIGNANT GROWTH
(CONT.)
4

5. BENIGN VS. MALIGNANT GROWTH
(CONT.)
Benign Tumor
• Does not have potential to kill host, but may
be life-threatening because of its location
• Does not invade adjacent tissue or spread to
distant sites
• Many are encapsulated
• More closely resembles original tissue type
• Grows more slowly, little vascularity, rarely
necrotic, often retains original function
5

6. BENIGN VS. MALIGNANT GROWTH
(CONT.)
Benign Tumor
• “-oma” suffix indicates benign tumor
(adenoma)
• “-carcinoma,” “-sarcoma” indicate
malignant tumors
• Carcinoma: malignant tumor of epithelial
origin (adenocarcinoma)
• Sarcoma: malignant tumor of mesenchymal
origin
• Leukemia: malignant growth of white blood
cells
6

7. EPIDEMIOLOGY AND CANCER
RISK FACTORS
• Cancer is 2nd leading cause of death in the
U.S.
• Most cancer deaths occur in individuals over
age 55
• Men have 1:2 risk of developing cancer;
women have 1:3 risk
• 5-year survival rate: 66%
7

8. EPIDEMIOLOGY AND CANCER
RISK FACTORS (CONT.)
8

9. EPIDEMIOLOGY AND CANCER
RISK FACTORS (CONT.)
• One third of cancer-related deaths may be
attributable to lifestyle factors
• Tobacco use
• Nutrition
• Obesity
• Sun exposure (skin cancer)
• Sexual exposure to HPV (cervical cancer)
• Early screening aids in early detection
9

10. TOBACCO USE
• Death rate from lung cancer has dramatically
increased (may be directly related to
smoking)
• Lung cancer: leading cause of death in men
and women; worst survival rate
• Also linked to pancreatic, kidney, bladder,
mouth, esophageal, and cervical cancers
10

11. TOBACCO USE (CONT.)
11

12. TOBACCO USE (CONT.)
• Two types of carcinogens
• Initiator (causes genetic damage)
• Promoter (promotes tumor growth)
• Tobacco smoke contains both types
• Second-hand smoke also increases risk for
lung cancer
12

13. TOBACCO USE (CONT.)
13

14. NUTRITION
• Dietary factors believed to be related to
cancer risk
• Fat
• Fiber
• Alcohol
• Antioxidants
14

15. GENETIC MECHANISMS OF
CANCER
• Carcinogen
• Potential cancer-causing agent
• Proto-oncogene
• Overactivity of cancer-critical genes contributes to
cancer
• Oncogene
• Proto-oncogene in its mutant overexpressed form
• Tumor suppressor gene
• Too little gene activity; inhibits cell proliferation
• Cancers may arise when tumor suppressor gene
function is lost or abnormally inhibited
15

16. PROTO-ONCOGENES
• Normal cellular genes that can be
transformed into oncogenes by activating
(gain-of-function) mutations
• Code for
• Growth factors
• Receptors
• Cytoplasmic signaling molecules
• Nuclear transcription factors
16

17. PROTO-ONCOGENES (CONT.)
17

18. GROWTH FACTORS (MITOGENS)
Small Cell−Manufactured Peptides
• Secrete into extracellular space
• Diffuse to nearby cells
• Interact with receptors on target cell surface
• Activate signaling cascade; can produce
autocrine signaling
18

19. GROWTH FACTOR RECEPTORS
• Transmembrane proteins
• Mitogen-binding area on outside of cell
• Enzyme-activating area on inside of cell
• Will bind with only one particular mitogen
• Binding activates cell proliferation
19

20. CYTOPLASMIC SIGNALING
PATHWAYS
• Involve numerous enzymes and chemicals
that normally function to transmit signals from
activated receptors at cell surface to cell
nucleus
• Mutant proto-oncogene can activate
pathway, even when no signal received at
cell surface
20

21. TRANSCRIPTION FACTORS
• Proteins that must be assembled at the
promoter area to begin gene transcription
• Normally sequestered and prevented from
indiscriminate activity until appropriate signals
cause their release
• Mutations may cause overproduction of
transcription factors
21

22. FROM PROTO-ONCOGENE TO
ONCOGENE
• Proto-oncogenes become activated
oncogenes when mutations alter their
activity so that proliferation-promoting
signals are generated inappropriately
• Oncogenes introduced to host cell by retrovirus
• Proto-oncogene within cell suffers a mutagenic
event
• DNA sequence may be lost/damaged and
allows proto-oncogene to become abnormally
active
• Error in chromosome replication causes extra
copies of proto-oncogene in the genome
22

23. FROM PROTO-ONCOGENE TO
ONCOGENE (CONT.)
23

24. FROM PROTO-ONCOGENE TO
ONCOGENE (CONT.)
• Retrovirus
• HIV
• Kaposi’s sarcoma
• Epstein-Barr virus
• Burkitt lymphoma
• Human T-lymphocyte virus type 1
• Adult T-cell leukemia/lymphoma
• Composed of RNA
• Contains reverse transcriptase enzyme
• Directs synthesis of a DNA copy of viral RNA
24

25. FROM PROTO-ONCOGENE TO
ONCOGENE TRANSCRIPTION
FACTORS
25

26. TUMOR-SUPPRESSOR GENES
• Contribute to cancer only when not present
• Both copies of tumor suppressor genes are
inactivated when cancer develops
• One can inherit a defective copy of tumor
suppressor gene from 1 or both parents
26

27. TUMOR-SUPPRESSOR GENES
(CONT.)
27

28. RB GENE
• Codes for large protein in cell nucleus
(pRb) that is the “master break” for the
cell cycle
• Blocks cell division
• Binding transcription factors
• Inhibits T factors from transcribing genes that
initiate cell cycle
• Can be induced to release transcription
factors when sufficiently phosphorylated
• An inactivating mutation of the Rb gene
removes 1 major restraint on cell division
28

29. RB GENE (CONT.)
29

30. P53 GENE
• Most common tumor-suppressor gene defect
identified in cancer cells
• More than ½ of all types of human tumors lack
functional p53
• Inhibits cell cycling
• Accumulates only after cellular (DNA)
damage
• Binds to damaged DNA and stalls division
30

31. P53 GENE (CONT.)
31

32. P53 GENE (CONT.)
• May direct cell to initiate apoptosis
• Allows genetically damaged/unstable cells to
survive and continue to replicate
• Chemotherapy/radiation
• Damages target cell to trigger p53-mediated cell
death
• Cancer cells that lack functional p53 may be
resistant to chemotherapy/radiation
32

33. BRCA1 AND BRCA2 GENES
• Breast cancer genes
• Family history and inherited defect in BRCA1
increases risk of breast and ovarian cancer
33

34. BRCA1 AND BRCA2 GENES
(CONT.)
34

35. MULTISTEP NATURE OF
CARCINOGENESIS
• Initiation
• Promotion
• Progression
35

36. MULTISTEP NATURE OF
CARCINOGENESIS (CONT.)
36

37. MULTISTEP NATURE OF
CARCINOGENESIS (CONT.)
37

38. INITIATION
• Initiating events
• Genetic mutations
• Inappropriately activate proto-oncogenes
• Inactivate tumor suppressor genes
• Proliferation
• Required for cancer development (nonproliferating
cells cannot cause cancer)
• Each type of cancer has its own combination
of mutations that lead to malignancy
38

39. INITIATION (CONT.)
39

40. INITIATION (CONT.)
• Complete carcinogens
• Capable of initiating cell damage as well as
promoting cellular proliferation
• Partial carcinogens
• Promoters that stimulate growth
• Incapable of causing genetic mutations sufficient to
singly initiate cancer
40

41. PROMOTION
• Stage during which mutant cell proliferates
• Activation of another oncogene
• Inactivation of tumor suppressor gene
• Nutritional factors
• Infection
• Regulated by many hormonal growth factors
(hormones may be promoters for certain
cancers)
• Estrogen
• Testosterone
41

42. PROGRESSION
• Mutant, proliferating cells begin to exhibit
malignant behavior
• Malignant cells commonly produce
telomerase (an enzyme that repairs telomeres
and may be a key for attaining immortality)
• Cells whose phenotype gives them a growth
advantage proliferate more readily
• Requires multiple steps
42

43. PROGRESSION (CONT.)
43

44. METASTASIS
• Process by which cancer cells escape their
tissue of origin and initiate new colonies of
cancer in distant sites
• Specialized enzymes and receptors enable them to
escape their tissue of origin and metastasize
44

45. METASTASIS (CONT.)
45

46. PATTERNS OF SPREAD
• Cancer cells generally spread via circulatory
or lymphatic systems
• Tumor markers help identify parent tissue of
cancer origin
• Rely on some retention of parent tumor
characteristics
• Some released into circulation
• Others identified through biopsy
• Enzymes typically used as tumor markers
• Help track tumor activity
46

47. ANGIOGENESIS
• Process by which cancer tumor forms new
blood vessels in order to grow
• Usually does not develop until late stages of
development
• Triggers are not generally understood
• Inhibition of angiogenesis is important
therapeutic goal
47

48. GRADING AND STAGING OF
TUMORS
• To predict clinical behavior of malignant
tumor and guide therapeutic management
• Grading
• Histologic characterization of tumor cells
• Degree of anaplasia
• 3 or 4 classes of increasing degrees of malignancy
48

49. GRADING AND STAGING OF
TUMORS (CONT.)
• Staging
• Location and patterns of spread within the host
• Tumor size, extent of local growth, lymph node and
organ involvement, distant metastasis
• TNM system most widely used
• Results of staging determine treatment
modality
49

50. GRADING AND STAGING OF
TUMORS

51. EFFECTS OF CANCER ON THE
BODY
• Depends on location of tumor and extent of
metastasis
• Early stages may be symptomatic
• Tumor increases in size and spreads; more
symptoms become apparent

52. EFFECTS OF CANCER ON THE
BODY (CONT.)

53. WARNING SIGNS OF CANCER
• Change in bowel or bladder habits
• A sore that does not heal
• Unusual bleeding or discharge
• Thickening or lump in breast or elsewhere
• Indigestion or difficulty swallowing
• Obvious change in wart or mole
• Nagging cough or hoarseness

54. WARNING SIGNS OF CANCER
IN CHILDREN
• Continued, unexplained weight loss
• Headaches with vomiting in the morning
• Increased swelling or persistent pain in bones
or joints
• Lump or mass in abdomen, neck, or
elsewhere
• Development of whitish appearance in pupil
of the eye
• Recurrent fevers not caused by infections
• Excessive bleeding or bruising
• Noticeable paleness or prolonged tiredness

55. PAIN
• Common and feared complication
• May be due to metastasis, tissue
destruction/inflammation
• May be caused by cancer treatment
• Usually controlled with analgesics

56. CACHEXIA AND IMMUNE
SYSTEM DEFICITS
• Cachexia
• Overall weight loss and generalized weakness
• Loss of appetite (anorexia)
• Increased metabolic rate
• Nausea/vomiting
• Immune system suppressed by cancer cell
secretions
• Some cancers can elude immune system
detection

57. BONE MARROW SUPPRESSION
• Contributes to anemia, leukopenia, and
thrombocytopenia
• Due to invasion and destruction of bone
marrow cells, poor nutrition, and
chemotherapy
• Anemia: Deficiency in circulating red blood
cells

58. LEUKOPENIA
• Deficiency in circulating white blood cells
• Primary cause
• Malignant invasion of bone marrow
• Contributing factors
• Malnutrition
• Chemotherapy
• Opportunistic organisms can only infect
immunocompromised host
• Infections difficult to manage, prevent

59. THROMBOCYTOPENIA
• Deficiency in circulating platelets
• Important mediators in blood clotting
• Predispose to life-threatening hemorrhage
• Anemia, leukopenia, thrombocytopenia can
all be managed by blood replacement
therapy

60. OTHER EFFECTS
• Hair loss and mucositis
• Complications of chemotherapy and radiation
therapy
• Mucositis primary source of cancer pain and anorexia
• May provide a portal for infection
• Paraneoplastic syndromes
• Hypercalcemia
• Cushing syndrome secondary to ACTH secretion
• Hyponatremia and water overload secondary to
excess ADH secretion

61. CANCER THERAPY
• Early detection best prognosis for cure
• Mainstays of therapy
• Surgery
• Radiation therapy
• Chemotherapy
• Drug therapy
• Emerging therapies
• Immunotherapy
• Targeted molecular therapies
• Stem cell transplantation

62. CANCER THERAPY (CONT.)

63. SURGERY
• Majority of patients with solid tumors are
treated surgically
• Main benefit: removal of tumor with minimal
damage to other body cells
• Lymph nodes biopsied and/or removed
• Commonly accompanied by radiation
therapy or chemotherapy

64. RADIATION THERAPY
• Kills tumor cells by damaging nuclear DNA
• Kills cells that are nonresectable due to
location, missed by surgery, or undetected
• May not kill cells directly, but initiates
apoptosis
• Small doses of radiation over several
treatments (difficult to kill at once because
cells on different cycles)
• Some normal cells killed during radiation
therapy

65. DRUG THERAPY
• Systemic administration of anticancer
chemicals to treat cancers known or
suspected to be disseminated in the body
• Finds cancer cell targets in the body
• Most are cytotoxic
• Not selective for tumor cells (normal cell
death may also occur)

66. DRUG THERAPY (CONT.)
• Most effective on rapidly dividing cells
• Several courses ensure all cancer cells killed
• Serious side effect: bone marrow suppression

67. IMMUNOTHERAPY
• Primarily involves use of:
• Interferons
• Glycoproteins produced by immune cells in response to
viral infection
• Interleukins
• Peptides produced and secreted by white blood cells
• Monoclonal antibodies
• Antibodies with identical structure that bind with
specific target antigens
• Generally used as adjuncts to surgery,
irradiation, and chemotherapy

68. GENE AND MOLECULAR
THERAPY
• May have high therapeutic potential
• May be used to suppress overactive
oncogenes or replenish missing tumor
suppressor function
• Current uses
• Genetic alteration of tumor cells to make them
more susceptible to cytotoxic agents or immune
recognition
• Genetic alteration of immune cells to make them
more efficient killers of tumor cells
• Can be directed at cells other than cancer
cells

69. STEM CELL TRANSPLANTATION
• Used to manage life-threatening disorders in
which patient’s bone marrow cannot
manufacture white blood cells, red blood
cells, or platelets
• Also applied to other malignancies and to
nonmalignant disorders
• Provides a method to restore bone marrow
function after high-dose irradiation or
chemotherapy