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CANCER
NEOPLASIA-IV
Nam Deuk Kim, Ph.D. 1
BIOLOGY OF TUMOR GROWTH
Transformation
Growth
Invasion
Metastases
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INCREASING ANEUPLOIDY EUPLOID CELL POPULATION
LIVER METASTASES
LUNG METASTASES
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아르헨티나에서 25kg짜리 초대형 암 덩어리 발견(2010.9.2)
2010년 8월 26일 54세 여성(가정주부)의 자궁암 수술(체중 140kg)
길이가 48cm에 무게가 25kg에 달하는 암 덩어리
부에노스 아이레스 근교 로마 데 자모라의 간둘포 병원에서 수술을 이끈 오스카 로페즈 박사
1991년 미국 캘리포니아에서 약 137kg짜리 종양이 제거된 기록이 있으며, 45kg 이상의 대형 종양들이 종종 발견돼 왔음
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Kinetics of Tumor Cell Growth: Simple Exponential Growth Model
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Simple Exponential Growth Model
1. Simple exponential growth
• A cell divides to produce two daughter
cells
increase in powers of 2
N = 2n(t)
• N = total number of cells
• n(t) = number of cell divisions that
have occurred by time t
• t = the cell cycle time (Tc) or the cell
generation time
• If a population grown exponentially
N = N0ekt
• N0 = starting number of cells (one cell,
in our case)
• k = the fraction of the population
dividing per unit time (hours,
commonly)
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• N(t) = N0ekt
N0: original cell number
k : the growth rate constant (hours)
• V(t) = V0ekt
• 3 ‘if’s
1. If all cancer cells are
proliferating,
2. 2. if they all have the same cell
cycle time, &
3. if there is no cell loss, then the
cell cycle time is equivalent to
the time required for the entire
population to double in size.
• It is called the population doubling
time, or TD
• Population doubling time (TD) is
given by
• V(t) = V0ekt 2V0 = V0e
kt 2 = ekt
kt = Ln2 (Ln2 = 0.693)
0.693 t = 0.693/k
TD = Tc = 0.693/k k = 0.693/TD
• V(t) = V0e(0.693/TD)
• If 1.0 g =~109 cells
109 = 1(e0.693/x);
X = t/TD
• Ln(109) = 0.693(X)
• X = 20.72/0.693
X = 29.9 doublings
If a mean doubling time is two
months 4.98 years to be detected
clinically.
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The Growth Curve of Human Tumors
Biology of tumor growth and heterogeneity
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Schematic representation of tumor growth
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Deviation: Gompertzian growth kinetics
Deviation: Gompertzian growth kinetics
Gompertzian equation
V(t) = V0e[(A/B)(1-e-t)]
a. At early time (small t)
V = V0e(At) : simple exponential
b. At late times (large t): maximum volume
V = V0e(A/B)
Decrease in the growth fraction
Increase in the cell loss factor, both most likely related to nutrient deficits secondary to insufficient vascularization
a. Programmed cell death (apoptosis)
b. Inadequate blood supply with consequent ischemia
c. A paucity of nutrients
d. Vulnerability to specific and nonspecific host defenses
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Tumor Angiogenesis (1) (VEGF, vascular endothelial growth factor
bFGF, basic fibroblast growth factor)
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Tumor Angiogenesis (2)
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Ma X, IOVS, 2004, 45:2915
Keywords in Angiogenesis
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- Late Juda Folkman, M.D.,
Ph.D. (1933-2008)
Cornea pocket assay (FGF)
Angiogenesis in tumor
www.medscape.com/ viewprogram/2629_pnt 17
Regulators of Angiogenesis 1. Angiogenic factors
(VEGF, FGF, Ang-2)
2. Proteases
(cathepsin, MMPs) 3. Cellular responses
4. Signaling enzymes
EC
PC
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The Metastatic
Cascade
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Mechanism of Invasion and Metastasis
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국내 첫 ‘암 전이 지도’ 나왔다 암 옮겨간 부위 폐 - 뼈 - 간 順
위암복막; 전립샘암뼈 “조심”
삼성서울병원은 1995∼2007년 이 병원에서 치료를 받은 위암, 간암, 폐암, 유방암, 자궁경부암, 대장암, 전립샘암 등 국내에서 발생빈도가 높은 7대 암 환자 8만7122명을 분석해 암이 어떤 장기와 조직으로 전이되는지를 보여 주는 ‘암 전이지도’를 처음으로 만들었음.
분석 결과 위암은 가까운 복막으로, 전립샘암은 뼈로 많이 전이되는 등 암마다 일정한 ‘전이 유형’이 있고 특히 위암은 암세포가 가까운 기관일수록 잘 전이되는 것으로 조사됨.
암 환자의 24.2%인 2만1120명에게서 전이가 발생함. 전체 전이건수는 총 3만1899건으로, 전이 환자 1인당 평균 1.5건의 전이가 발생했음.
7대 암 중 전이가 가장 많이 발생하는 암은 대장암(34.7%)이며 전이율이 가장 낮은 암은 전립샘암이었음.
암이 가장 잘 전이되는 기관은 폐(20.9%), 뼈(20.7%), 간(19.8%) 등의 순이었고 전립샘, 식도, 췌장 등의 부위는 암 세포가 잘 전이되지 않는 것으로 조사됨.
박세훈 삼성서울병원 혈액종양내과 교수는 “암이 왜 전이되는지에 대해 의학적으로 규명되지 않았지만 암의 전이지도를 알고 있으면 전이 증세가 나타났을 때 신속하게 대처할 수 있다”고 함.
동아일보 (2008-04-03) 21
Tumor-specific antigens (TSAs): only on
tumor cells
Tumor-associated antigens (TAAs): present
on tumor cells and also on some normal cells
HOST DEFENSE AGAINST
TUMORS – TUMOR IMMUNITY
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The ability of an animal to resist a live tumor
implant after previous immunization with live or
killed tumor cells.
The ability of tumor-free host animals to resist
challenge when infused with sensitized T cells from
a tumor-immunized syngeneic donor
The demonstration in vitro of tumor cell destruction
by cytotoxic CD8+ T cells derived from a tumor-
immunized animal.
Tumor antigenicity
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TSAs
Tumor-specific shared antigens: MAGE, GAGE, BAGE, & RAGE
Tissue-specific antigens: tyrosinase-derived peptides
Antigens resulting from mutations: mutated 53, K-ras, CDK4, bcr-c-abl gene products
Overexpressed antigens: c-erbB2 (or neu)
Viral antigens: E7 protein of HPV-16
Other tumor antigens: oncofetal antigens (AFP); carcinoembryonic antigen (CEA); differentiation antigens
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Molecular mechanisms underlying the formation of
tumor antigens recognized by CD8+ T cells (1):
Tumor-Specific Shared Antigens
MAGE-1 (melanoma antigen-1): 37% of melanomas; lung, liver,
Liver, stomach, esophagus, and urinary bladder
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Molecular mechanisms underlying the formation of
tumor antigens recognized by CD8+ T cells (2):
Tissue-Specific Antigens
Tyrosinase-derived peptides
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Molecular mechanisms underlying the formation of
tumor antigens recognized by CD8+ T cells (3):
Antigens Resulting From Mutations
Mutated p53, K-ras, CDK3, and bcr-c-abl gene products
27
Molecular mechanisms underlying the formation of
tumor antigens recognized by CD8+ T cells (4):
Overexpressed Antigens
c-erbB2 (or neu) protein
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Molecular mechanisms underlying the formation of
tumor antigens recognized by CD8+ T cells (5):
Viral Antigens
E7 protein of HPV-16
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Antitumor
Effector
Mechanisms
•Cytotoxic T lymphocytes
•Natural killer cells
•Macrophages
•Humoral
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Mechanisms to escape or evade
the immunosurveillance of host by
tumor cells
Selective outgrowth of antigen-negative variants: eliminate immunogenic subclone
Loss or reduced expression of histocompatibility antigens: no HLA class I molecule
Lack of costimulation: no costimulatory molecules
Immunosuppression: TGF- (potent immunosuppressant)
Apoptosis of cytotoxic T cells: Fas ligand
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CLINICAL FEATURES OF TUMORS (1)
Effects of Tumor on Host
a. Local and hormonal effects
a) obstruction
b) ulceration
c) hormone production
b. Cancer cachexia: weakness, anorexia,
and anemia
c. Paraneoplastic syndromes
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Paraneoplastic syndromes
Endocrinopathies
Nerve and muscle syndromes
Dermatologic disorders
Osseous, articular, and soft tissue changes
Vascular and hematologic changes
Others
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Endocrinopathies
Cushing syndrome
Syndrome of inappropriate antidiuretic
hormone secretion
Hypercalcemia
Hypoglycemia
Carcinoid syndrome
Polycythemia
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CLINICAL FEATURES OF TUMORS (2)
Grading and Staging of Tumors
T: primary tumor
N: lymph node involvement
M: metastasis
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5 Year Survival Rate
95% 85% 50%
35%
Stomach
Ca.
36
(1998-2000)
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2008년 10월 16일 보건복지가족부
2001∼2005년 발생한 암환자 57만6479명을 추적 조사한 결과 5년 생존율이 52.2%로 집계됨. 38
위암 완치율, 1기 발견땐 4기의 ‘17배’
동아일보 2008. 11. 11
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난치암의 5년 생존율 변이
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Laboratory Diagnosis of Cancer
Histologic and Cytologic Methods
Immunocytochemistry
Molecular Diagnosis: PCR, FISH
Flow Cytometry: TSA, DNA content
Tumor Markers
Radiogenic Diagnosis: X-ray, CT, MRI
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X-rays
Barium contrast X ray
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Common Scanning Techniques
1. Computerized
Tomography
(CT)
2. Magnetic Resonance
Imaging (MRI)
3. Ultrasound
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Spiral-CT
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1. Digital subtraction angiography (DSA)
2. Positron-emission tomography (PET)
3. PET-CT
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Histologic and Cytologic Methods
Normal cervicovaginal smear Abnormal cervicovaginal smear
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Antikeratin immunoperoxidase stain of
an undifferentiated tumor (carcinoma)
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Markers Associated Cancers
Hormones
Human chorionic gonadotropin
Calcitonin
Oncofetal Antigens
-fetoprotein (AFP)
Carcinoembryonic antigen (CEA)
Isoenzymes
Prostatic acid phosphatase
Neuron-specific enolase
Specific Proteins
Immunoglobulins
Mucins and Other Glycoproteins
CA-125
CA-19-9
CA-15-3
Trophoblastic tumors
Medullary carcinoma of thyroid
Liver cell cancer
Ca. of colon, pancreas, lung, stomach
Prostate cancer
Small cell cancer of lung, neuroblastoma
Multiple myeloma and other gammopathies
Ovarian cancer
Colon cancer, pancreatic cancer
Breast cancer
Selected Tumor Markers
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Prostatic acid phosphatase
(PSA)
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Muriel Humphrey Brown
Vice president, USA
1967: Urine blood
1976: Bladder cancer
Radiation therapy &
Radical surgery
1994: 27-year-old urine
sample from Johns
Hopkins University
School Medicine
51
1976
1967
52
TREATMENTS OF TUMORS
Surgical removal
Anti-cancer chemotherapy
Radiotherapy
Immunotherapy
Bone marrow transplantation
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Chemotherapy and Radiation Kill
Cancer Cells
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Radiation therapy Used when cancer is small or has not spread
Radioisotopes used, e.g., Ra-226 and Co-60
Chemotherapy and radiation
destroy healthy cells
More precise treatments Monoclonal antibody treatment
Interferon treatment; limited at present
Radiotherapy (1)
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Radiotherapy (2)
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Antitumor
Effector
Mechanisms
Cytotoxic T lymphocytes
Natural killer cells
Macrophages
Humoral
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Bone Marrow Transplantation
• Breast cancer
• Non-Hodgkin’s lymphoma
• Acute myelogenous
leukemia
• Chronic myelogenous
leukemia
• Other Malignancies
• Acute lymphoblastic
leukemia
• Hodgkin’s disease
• Nonmalignant disease 58
Alternative Treatments (1)
Antineoplastons are peptides (bits of protein) that their discoverer, Stanislaw R. Burzynski of the Burzynski Research Institute in Houston, asserts can slow or reverse tumor growth. The National Cancer Institute (NCI) started a clinical trial of antineoplaston therapy in 1993; the project foundered when Burzynski and NCI investigators disagreed on treatment protocols and criteria for selecting patients
59
Alternative Treatments (2)
Gerson Therapy, after Max B. Gerson, is based on hourly consumption of crushed fruits and vegetables to correct alleged physiological imbalances. Coffee enemas are given to remove dead cells and toxins, and patients receive nutritional supplements as well. Several independent evaluations of case records have concluded that it has no discernible effectiveness.
60
Alternative Treatments (3)
Hydrazine sulfate, a compound studied
in Leningrad for more than 20 years,
may reverse cachexia, the wasting of
cancer patients’ bodies. Modest
improvements in survival (but no
remissions) have been documented.
61
Alternative Treatments (4)
Orthomolecular therapy, originally
developed by the late Nobelist Linus
Pauling, requires consumption of
megadoses of vitamin C in an effort to
aid the body’s repair systems. NCI-
sponsored trials did not demonstrate
any superiority to placebos.
62
Alternative Treatments (5)
Psychological interventions (including Simonton therapy, after O. Carl Simonton, and Bernard S. Siegel’s Exceptional Cancer Patients program) use combinations of meditation, visualization, therapy, support groups and other exercises. No definitive studies of their impact on survival have been conducted. Some physicians accept these techniques as adjuncts to conventional cancer therapy because they enhance patients’ sense of well-being.
63
Alternative Treatments (6)
Shark Cartilage, which has "anti-angiogenic" material (a substance that prevents the production of blood supply), is used to halt the cancerous tumors' supply of blood which ultimately kills the cancerous tumors by stopping their growth. In a study, patients, who had various forms of cancer, received the shark cartilage through an enema injection (an injection in the rectum). Scientists observed that thirty to one-hundred percent tumor reductions occurred within seven out of eight patients.
64
Alternative Treatments (6)
714X is a proprietary injection said to
contain compounds that mobilize the
immune system against cancer.
Samples analyzed by the Food and
Drug Administration contained only
camphor and water
65
Alternative Treatments (7)
Laetrile, which is often referred to as vitamin B17 (amygdalin), is a type of therapy that may not be effective all of the time. In a study using lab mice, laetrile(an almost nontoxic chemical) initiated antibody production, which fought breast tumors, when it was used with vitamin A as well as specific enzymes. Seventy-six percent of the mice breast tumors regressed. In a human study conducted between 1975 and 1977, out of twelve patients who received laetrile therapy, only three patients were cured, two patients received little results with the use of laetrile and chemotherapy and/or surgery
simultaneously, while seven patients died.
66
Alternative Treatments (8)
Boston University Medical Center
alternative cancer treatment
http://web.bu.edu/COHIS/cancer/
about/alttx/about.htm
67
