1 Chapter 5. Neoplasia23 Neoplasia?

Neoplasm (신생물)= Neo (new) + plasm (thing formed)Tumor (종양): benign (양성) or malignant (악성)

Cancer (암) = malignant tumor4 Cancer means ‘crab’5 1. Benign Versus Malignant Tumors (양성 대 악성 종양)

Benign (양성) tumors do not penetrate (침투) [invade 침윤] adjacent tissue borders, nor do they spread (metastasize, 전이) to distant sites.By contrast, malignant (악성) tumors, or cancers (암), have the added property of invading contiguous tissues and metastasizing to distant sitesThe terms benign and malignant refer to the overall biological behavior of a tumor rather than to its morphologic characteristics.In most circumstances, malignant tumors kill, whereas benign ones spare the host: However, so-called benign tumors in critical locations can be deadly.

6789 2. Classification of Neoplasms (신생물의 분류)

The suffix “oma” for benign tumors is preceded by reference to the cell or tissue of origin.chondroma (연골종) - chondrocyteepithelioma (상피종) - squamous epithelium

→ papilloma (유두종) - frond-like→ adenoma (샘종) - gland: e.g. thyroid adenoma

polyp (용종) - projected from mucus membraneteratoma (기형종) - arise from germ cells and contain derivatives of different germ layers

10 2.2 Malignant Tumors are Mostly Carcinomas or Sarcomas

10 2.2 Malignant Tumors are Mostly Carcinomas or Sarcomas (악성 종양은 대부분 암종 혹은 육종이다)The suffix “carcinoma” is applied to epithelial cancers and “sarcoma” to those of mesenchymal origin.

e.g. adenocarcinomasquamous cell carcinomachondrosarcoma

Exceptions!! - Historical terms: all of the following are highly malignant !!

hepatoma (간암): livermelanoma (흑색종): melanocyteseminoma (정상피종, 고환종): testeslymphoma (림프종): lymphatic cellleukemia (백혈병): -emia → tumors in hematopoietic cells

11 2.2 Malignant Tumors are Mostly Carcinomas or Sarcomas (악성 종양은 대부분 암종 혹은 육종이다)Secondary descriptors

papillary 유두상: frond-likemedullary 수질성: soft, cellular tumor with little connective tissue stromascirrhous 경화/desmoplastic 결합조직형성: a dense fibrous stroma

12 Leukemia vs. LymphomaBoth are cancers that affect a part of a human’s immune system.Leukemia 백혈병 (Leuk- white + emia blood): abnormal production of anomalous white blood cells.

the damaged bone marrow makes abnormal white blood cells, which do not die when they should, thus overcrowding the system (Thus ‘white’). → They will ultimately crowd out the normal blood cells and inhibit their function → lack of platelets......

Lymphoma 림프종: a tumor of the lymph nodes that causes lymph nodes to expand. the Hodgkin’s Lymphoma and the non-Hodgkin’s Lymphoma.

13 3. Histologic Diagnosis of Malignancy (악성 종양의 조직학적 진단)No reliable molecular indicators of malignancy → microscopy!3.1 Benign Tumors Resemble Their Parent Tissue (양성 종양은 그들의 원조직과 닮아 있다.)

Fig. 5-6 Lipoma (지방종) →

3.1 Benign Tumors Resemble Their Parent Tissue (양성 종양은 그들의 원조직과 닮아 있다.)

Fig. 5-6 Lipoma (지방종) → 14 3.2 Malignant Tumors Depart from the Parent Tissue Morphologically and Functionally (악성 종양은 형태학적으로 또한 기능

적으로 원조직으로부터 벗어나 있다.)Histologic features of malignancy 악성종양에서 나타나는 조직학적 특성1) Anaplasia 역형성 or cellular atypia 세포 비정형: next slide2) Mitotic activity 유사분열 활성: abundant mitoses3) Growth pattern 성장 형태: disorganized, random4) Invasion 침윤: into blood vessels, lymphatics5) Metastases 전이

15 3.2 Malignant Tumors Depart from the Parent Tissue Morphologically and Functionally (악성 종양은 형태학적으로 또한 기능적으로 원조직으로부터 벗어나 있다.)Anaplasia (역형성, ana (up, above) + plasia) → dedifferentiation: Cytologic evidence of anaplasia

① Pleomorphism (다형성, pleo-: more) 세포 및 세포핵의 크기와 모양의 다양성② Hyperchromasia 크고 과염색된 상태의 핵③ Atypical mitoses 비정형적인 유사 분열④ Giant cells 종양 거대 세포 (Figure 5-7B)

16 3.3 Immunohistochemical Tumor Markers are Antigens that Point to the Origin of Neoplasms (면역조직화학적 종양표지자는 신생물의 기원 을 알려주는 항원이다.)The ultimate tumor marker would be one that allows the unequivocal distinction between benign and malignant cells, but unfortunately no such marker exists.Nevertheless, some markers are often useful in identifying the cell of origin of a metastatic or poorly differentiated primary tumor.

PSA (Prostate-specific antigen, 전립선-특이적 항원): Prostate cancerCEA (Carcinoembryonic antigen, 암태아성항원): Colon cancerAFP (Serum α-fetoprotein, 혈청 α-태아단백): Liver cancer

1718 4. Invasion and Metastasis (침윤과 전이)

18 4. Invasion and Metastasis (침윤과 전이)Most carcinomas begin as localized growths confined to the epithelium → As long as these early cancers do not penetrate the basement membrane, such tumors are termed carcinoma in situ (제자리 암종).When the in situ tumor acquires invasive potential and extends directly through the underlying basement membrane, it can compromise neighboring tissues and metastasize.

1920 4.2 Metastatic Spread is the Most Common Cause of Cancer Death (전이는 암 사망의 주요 원인이다.)

Metastasis refers to the transfer of malignant cells from one site to another not directly connected with it.(1) Hematogenous Metastases (혈행성 전이)

Cancer cells commonly invade capillaries and venules, whereas thicker-walled arterioles and arteries are relatively resistant.

21 4.2 Metastatic Spread is the Most Common Cause of Cancer Death (전이성 확산이 암 사망의 주요 원인이다.)2) Lymphatic Metastases (림프성 전이)Basement membranes are lacking in lymphatic capillaries. Thus, invasive tumor cells may penetrate lymphatic channels more readily than blood vessels.Lymph nodes bearing metastatic deposits may be enlarged to many times their normal sizeBreast cancer: the initial metastases are almost always lymphatic

22 4.2 Metastatic Spread is the Most Common Cause of Cancer Death (전이성 확산이 암 사망의 주요 원인이다.)3) Seeding of Body Cavities (체강으로 파종)Malignant tumors that arise in organs adjacent to body cavities (e.g., ovaries, gastrointestinal tract, and lung) may shed malignant cells into these spaces.Such body cavities principally include the peritoneal and pleural cavities, although occasional seeding of the pericardial cavity, joint space, and subarachnoid space are observed.Tumors in these sites grow in masses and may provoke the formation of fluid (e.g., ascites [복수], pleural fluid [늑막액]), sometimes in very large quantities.

23 4.3 Invasion and Metastasis are Multistep Events (침윤과 전이는 다단계 과정을 거친다)① Invasion of the basement membrane underlying the tumor② Movement through extracellular matrix ③ Penetration of vascular or lymphatic channels

① Invasion of the basement membrane underlying the tumor② Movement through extracellular matrix ③ Penetration of vascular or lymphatic channels ④ Survival and arrest within circulating blood or lymph nodes ⑤ Exit from the circulation into a new tissue site⑥ Survival and growth as a metastasis, a process that involves angiogenesis

single cancer cell (monoclonal origin of tumors, 종양의 단클론 기원) → subpopulations with diverse biological characteristics and profound variations in their metastatic potential (tumor heterogeneity, 종양 이질성).

24 4.3 (1) Invasion (침윤)In epithelial tumors, invasion requires disruption of, and penetration through, the underlying basement membrane 바닥막 and passage through the extracellular matrix.1. Adhesion molecules (부착 분자): invasion requires expression of adhesion molecules by the malignant cells.: Integrins (cell-cell, cell-matrix), Immunoglobulin super family (ICAM-1), Cadherin (cell-cell zipper interaction), 2. Growth factors and Cytokines (성장인자와 시토카인): enhance proliferation, migration, and invasive properties of the tumor cells.3. Proteolytic enzymes (단백분해 효소): urokinase-type plasminogen activator (u-PA) and MMPs (collagenases)

25 4.3 (2) Metastasis (전이)1. Invasion of the circulation (순환계로의 침윤): After invading interstitial tissue, malignant cells penetrate lymphatic or vascular channels.: Most tumor cells do not survive their journey in the bloodstream, and less than 0.1% remain to establish a new colony.2. Escape from the circulation (순환계에서의 도피): tumor cells eventually extravasate by mechanisms similar to those responsible for local invasion3. Local growth (국소 성장): a new vascular supply is necessary for the tumor to grow to a diameter greater than 0.5 mm. → angiogenesisThe establishment of a metastatic colony does not mean that it inevitably enlarges → tumors may recur locally or at metastatic sites many years after the primary cancer has been surgically removed.e.g. tumor dormancy (종양의 동면상태): 20년 이상 완치된 것으로 보이다 갑자기 재발하는 현상

26 4.3 (3) Target Organs in Metastatic Disease (전이 질환에서의 표적 기관))The distribution of metastases: anatomical factors? or desired tissue (seed and soil)?→ it depends on tumor!

26 4.3 (3) Target Organs in Metastatic Disease (전이 질환에서의 표적 기관))The distribution of metastases: anatomical factors? or desired tissue (seed and soil)?→ it depends on tumor!

breast, prostate, thyroid cancer: metastasize to bone (favored 'soil'), not to spleen, skeletal muscleHowever, malignant tumors of the gastrointestinal tract commonly metastasize to the first capillary bed they encounter, namely the liver.

An additional factor that regulates homing of malignant cells may be the expression of complementary adhesion molecules, either by the cancer cells or those of the organ to which they home.

27 5. The Grading and Staging of Cancers (암의 등급과 병기)5.1 Cancer Grading Reflects Cellular Characteristics (암의 등급[분화도]은 세포 특성을 나타낸다)low-grade (낮은 등급): well-differentiated 분화가 잘 된high-grade (높은 등급): anaplastic 역형성 상태Cytologic and histologic grading are based on the degree of anaplasia and on the number of proliferating cells.

The degree of anaplasia: functioning glandlike structures in adenocarcinomas, epithelial pearls in squamous carcinomas → well-differentiated !!Evidence of abnormal or rapid growth: a) large numbers of mitoses (많은 수의 유사분열), b) atypical mitoses (비정형유사분열) c) nuclear pleomorphism (핵의 다형태성), d) tumor giant cells (종양거대세포)

2829 5.2 Cancer Staging Refers to the Extent of Spread

(암의 병기는 확산 정도를 말한다)TNM cancer staging system (TNM 암병기 체계)

“T” refers to the size of the primary tumor 원발종양의 크기: T1-T4, Tis (carcinoma in situ), TX (cannot be evaluated), T0 (No Tumor) “N” to regional lymph node metastases 국소 림프절 전이: N1-N3, NX, N0“M” to the presence and extent of distant metastases 전이의 유무: MX, M0, M1

30 6. The Clonal Origin of Cancer (암의 클론 기원)

30 6. The Clonal Origin of Cancer (암의 클론 기원)most cancers arise from a single transformed cell.

Glucose-6-phosphate dehydrogenase (G6PD)Barr body (바소체, 성염색질): inactivated X-chromosome, randomly selected during embryonic development.leiomyomas: leio- (smooth) + myo- (muscle): leiomyomas of the uterus have been shown to contain one or the other isozyme (A or B) but not both.

31 7. The Growth of Cancers (암의 성장)Historically, it was once believed that neoplastic cells divide at a faster rate than normal ones.However, it is now clear that tumor cells do not necessarily proliferate more rapidly than normal ones: more cells are produced than die in a given time.

7.1 Tumor Growth Rates May be Expressed as Doubling Times (종양의 성장속도는 두 배로 증식하는 시간으로 표현 가능하다)

1 g (1 cm3) cancer = 108~109 cells, at least 30 doubling times.1 kg = 1012 cells, only 10 additional doubling times.the actual doubling time of human tumors is highly unpredictable.

3233 7.2 Tumor Angiogenesis Refers to the Sprouting of New Capillaries (종양의 혈관신생은 새로운 모세혈관이 자라 나는 것을 말한

다)In the absence of new vessels, malignant tumors do not grow larger than 1 to 2 mm in diameter.the density of capillaries within the primary tumor (원발성종양) correlates directly with metastases and decreased host survival.tumor angiogenesis occurs in non-neoplastic host tissue and is comparable to that in wound healingVEGF, FDF-2 → stimulates angiogenesis: inhibitor of these factors also suppress many solid tumors as well.

34 8. The Molecular Genetics of Cancer (암의 분자 유전학)Cancer cell ← somatic mutations in genes that control cell growth, differentiation, and apoptosis, or that maintain genomic integrity.* somatic mutation = gene changes that are not passed on to its offspring through the germ-line.* germ-line mutation = gene changes in germ cells (oocyte, sperm) which often transmitted to offsprings.

Similar mutations may also be present in the germ line of persons with hereditary cancer predispositions.Mutations can also be environmental (chemical, radiation, ROS)

Similar mutations may also be present in the germ line of persons with hereditary cancer predispositions.Mutations can also be environmental (chemical, radiation, ROS)The most common mechanism of mutagenesis relates to spontaneous errors in DNA replication and repair.

it has been estimated that humans acquire about 175 mutations per generation.If the mutation involves genes that control growth or stabilize the genome, it may give rise to a clone of cells that possess a growth advantage over their normal neighbors. Successive mutations in similar genes result in increasingly aberrant clones until a malignant phenotype eventually emerges.

35 8.1 Transformed Cells Share Common Attributes (변형된 세포는 공통된 속성을 공유한다)Cancer cells: 4 to 7 mutated genes, or more → multistep process over yearsThe normal genes that are mutated in various cancers, include cell cycle regulators, signal transduction factors, transcriptional factors, DNA-binding proteins, growth factor receptors, adhesion molecules, effectors of apoptosis, and telomerase. Such “transforming genes” can be grouped into three categories:

36 8.2 Oncogenes are Counterparts of Normal Genes (종양유전자는 정상유전자에 대응된다.)Oncogene: a gene that has the potential to cause cancer

c.f. proto-oncogene: a normal gene that can become oncogene(1) Mechanisms of Activation of Cellular Oncogenes (세포 내 종양유전자의 활성화 기전)

① mutation② chromosomal translocation③ gene amplification

37 ① Activation by Mutation"gain-of-function" mutations in protooncogenes: usually somatic alteration rather than germ-line one.Germline mutations in protooncogenes are often lethal in utero except...

c-ret: heritable endocrine cancersc-met, which encodes the receptor for hepatocyte growth factor, is associated with a hereditary form of renal

c.f. c- (counterpart) vs. v- (viral)38 ② Activation by Chromosomal Translocation 염색체 전위

Germline mutations in protooncogenes are often lethal in utero except...c-ret: heritable endocrine cancersc-met, which encodes the receptor for hepatocyte growth factor, is associated with a hereditary form of renal

c.f. c- (counterpart) vs. v- (viral)38 ② Activation by Chromosomal Translocation 염색체 전위

1) Philadelphia chromosome: found in 95% of patients with chronic myelogenous leukemia (만성 골수성 백혈병)

c-abl → bcr/abl fusion gene

39 ② Activation by Chromosomal Translocation2) Burkitt lymphoma

c-myc protooncogene → translocated next to genes that control transcription of immunoglobulin light or heavy chains → overproduction of a normal c-myc → promotes the emergence of a dominant clone of B cells, driven relentlessly to proliferate as a monoclonal neoplasm.

40 ③ Activation by Gene Amplification 유전자 증폭The erb B protooncogene is amplified in up to one third of breast and ovarian cancers.erb B2 = Her2/neu: a receptor-type tyrosine kinase that resembles EGF receptor

Amplification of Her2 in breast and ovarian cancer may be associated with poor overall survival and decreased time to relapse.

Trastuzumab (Herceptin): an antibody targeted against Her241 (2) Mechanisms of oncogenes action

(종양유전자의 작용 기전)Oncogenes can be classified into...

growth factor (1)transmembrane growth factor receptor (tyrosine kinase, 2)membrane-associated kinases (3)ras GTPase family (4)cytoplasmic kinases (5)nuclear transcriptional regulators (6)

42 (2) Mechanisms of oncogenes action (종양유전자의 작용 기전)

42 (2) Mechanisms of oncogenes action (종양유전자의 작용 기전)

A. Oncogenes and Growth Factorsc-sis encodes PDGF (platelet-derived growth factor), a potent mitogen for fibroblasts, smooth muscle cells, glial cells → sarcoma, glioblastoma

B. Oncogenes and Growth Factor ReceptorsUnder normal circumstances, binding of a growth factor to its receptor activates the cytoplasmic tyrosine kinase domain, after which the receptor reverts to its resting state.Mutation in growth factor receptor results in unrestrained (constitutive) activation of the receptor.e.g. germline point mutation in c-ret: constitutive activation of the receptor → endocrine neoplasia, familial medullary thyroid carcinoma

43 (2) Mechanisms of oncogenes action (종양유전자의 작용 기전)

C. Ras Oncogenesras: the most frequent dominant mutation in human cancers

ras encodes p21 → mutaion of p21: no GTPases activity → always 'on'D. Bcl-2 and Apoptosis

Bcl-2 and its family regulate the permeability of mitochondrial membranes: Bcl-2 itself exerts an antiapoptotic effect by preventing the release of cytochrome c, thereby protecting the cell from the mitochondrial apoptotic pathway → neoplasm accumulation by overexpression of Bcl-2

44 8.1 Transformed Cells Share Common Attributes (변형된 세포는 공통된 속성을 공유한다)“Transforming genes” in cancer can be grouped into three categories:

45 8.3 Tumor Suppressor Genes Negatively Regulate Cell Growth (종양억제유전자는 세포 성장을 음성적으로 조절한다.)Tumor suppressors ≅ "gate keepers" ≅ loss of function mutationTumor suppressors are in fact growth suppressorsBoth alleles of tumor suppressor genes must be inactivated to become functionally dominant

heterozygosity is sufficient to protect against cancerloss of heterozygosity predisposes to tumor development

46 8.3 (1) The Role of Tumor Suppressor Genes in Carcinogenesis:

46 8.3 (1) The Role of Tumor Suppressor Genes in Carcinogenesis: Retinoblastoma (망막아세포종): a rare childhood cancerRb gene is located on the long arm (q) of chromosome 13.40% of cases are associated with a germline mutation; the remainder are sporadic

a. sporadic case of retinoblastoma: the incidence of sporadic retinoblastoma is very low (1/30,000).b. hereditary case of retinoblastoma: heterozygote state (no observable changes in the retina) → if normal Rb is inactivated then retinoblastoma occurs: two-hit hypothesis

Children who inherit a mutant Rb gene also suffer a 200-fold increased risk of developing mesenchymal tumors in early adult life. Rb gene is also related with more than 20 different cancers.Inactivated Rb gene allows unregulated cells to exit G1 restriction (R) checkpoint and proceed to G1–S phase human DNA viruses (e.g., human papillomavirus [HPV]) inactivate Rb, thereby leading to dysregulated cell growth.

47 Cell Cycle4849 8.3 (1) The Role of Tumor Suppressor Genes in Carcinogenesis:

p53: a principal mediator of growth arrest, senescence, and apoptosis.thus, loss of p53 function → cancer

cell damage, stress → ↑p53 → ↑cyclin–dependent kinase (CDK) inhibitors → cells are 'arrested' in G1/S check point → give enough time for cell to repair DNA damage or apoptosis.p53 acts as a “guardian of the genome” by restricting uncontrolled cellular proliferationmutations of p53 seem to be the most common genetic change in human cancer.

deletion of both p53 → cancerhowever, one normal/one mutant → a mutant allele inactivates the normal one: dominant negative geneLi-Fraumeni syndrome: an inherited predisposition to develop cancers in many organs due to germline mutations of

5051 8.3 (1) The Role of Tumor Suppressor Genes in Carcinogenesis:

APC (Adenomatous polyposis coli) gene: implicated in the pathogenesis of familial adenomatous polyposis coli (샘종성 결장폴립증) and most sporadic colorectal cancers: APC gene product binds and inhibits the function of β-catenin

APC (Adenomatous polyposis coli) gene: implicated in the pathogenesis of familial adenomatous polyposis coli (샘종성 결장폴립증) and most sporadic colorectal cancers: APC gene product binds and inhibits the function of β-catenin

The gene products of oncogenic DNA viruses lead to the inactivation of tumor suppressor proteins.e.g. HPV → p53

SV40, adenovirus, HPV, HHV-8 → Rb

52 8.1 Transformed Cells Share Common Attributes (변형된 세포는 공통된 속성을 공유한다)“Transforming genes” in cancer can be grouped into three categories:

53 8.4 DNA Repair Genes Protect the Integrity of the Genome (DNA 복구유전자는 게놈의 완전한 상태를 보호한다.)

The third class of genes related in cancer: mutator genes 돌연변이유발유전자 or caretaker genes 관리자? (돌보는 사람)→ mutator genes are ones involved in DNA repair

Think of a "spell-checker"The loss of the mutator gene function → accumulation of mutations → ↑cancer

e.g. 5% of hereditary nonpolyposis colon cancer (유전성 비폴립성 대장암, = Lynch syndrome), which are not associated with APC

54 8.5 Telomerase is Activated in Most Cancers(끝분절효소는 대부분의 암에서 활성화되어 있다)As cells in tissue culture continue to divide, the tips of the chromosomes, termed telomeres (끝분절, 종말체), progressively shorten.Somatic cells do not normally express telomerase (끝분절효소), an enzyme that recognizes the end of a chromosome and adds repetitive telomeric sequences to maintain telomere length.Most cancer cells activates telomerase reverse transcriptase, a subunit of telomerase.Telomerase is not classified as an oncogene because it does not lead to growth deregulation.

Many immortalized cell lines that express telomerase show no evidence of neoplastic capacity.55 8.1 Transformed Cells Share Common Attributes

Many immortalized cell lines that express telomerase show no evidence of neoplastic capacity.55 8.1 Transformed Cells Share Common Attributes

(변형된 세포는 공통된 속성을 공유한다)“Transforming genes” in cancer can be grouped into three categories:

56 9. Viruses and Human Cancer (바이러스와 인간의 암)Despite the existence of viral oncogenes, the number of human cancers definitely associated with viral infections is

Human T-cell leukemia virus type I (HTLV-I) (RNA retrovirus): T-cell leukemia/lymphomaHuman Papilloma Virus (HPV, DNA virus): cervical cancerHepatitis B Virus (HBV, DNA virus) & HBC (RNA): hepatomaEpstein-Barr Virus (EBV, DNA virus): lymphoma, nasopharygeal carcinomaHuman herpesvirus 8 (HHV, DNA virus): Kaposi sarcoma

57 9.1 Human T-Cell Leukemia Virus-I (HTLV-I) is a Lymphotropic Agent (HTLV-I은 림프구 친화 바이러스이다)adult T-cell leukemia

HTLV-I is tropic for CD4+ T lymphocytestropic = have an affinity to something 친화성

It is estimated that leukemia develops in less than 5% of persons infected with HTLV-I and exhibits a latency period on the order of 40 years for its development.HTLV-I is mediated principally by the viral transcriptional activation protein tax. → increases the transcription from its own viral genome, but also promotes the activity of other genes involved in host cell proliferation.

58 9.2 DNA Viruses Encode Proteins that Bind Regulatory Proteins (DNA 바이러스는 조절 단백질에 결합하는 단백질을 암호화한다)Oncogenic DNA viruses inactivate specific host proteins (e.g., Rb, p53) involved in the regulation of cell proliferation and apoptosis.(1) Human Papilloma Viruses (HPVs, 인유두종 바이러스)

induce lesions in humans that progress to squamous cell carcinoma.20 HPV types are associated with cancer of the uterine cervix, especially HPV 16 and 18The major oncoproteins encoded by HPV are E6 and E7.→ E6 binds to p53 and targets it for degradation & E7 binds to Rb.

59 But now we have vaccines !!Cervarix (GSK)Gardasil (MSD)

Cervarix (GSK)Gardasil (MSD)

60 9.2 DNA Viruses Encode Proteins that Bind Regulatory Proteins (DNA 바이러스는 조절 단백질에 결합하는 단백질을 부호화한다)

(2) Epstein-Barr Virus (EBV, 엡스타인-바 바이러스)So widely disseminated that 95% of adults in the world have antibodies against it.EBV infects B lymphocytes, transforming them into lymphoblasts with an indefinite lifespan.

Burkitt Lymphoma (버킷 림프종)Polyclonal Lymphoproliferation in Immunodeficient States (면역결핍 상태의 다클론성 림프구 증식)Nasopharyngeal Carcinoma (비인두암종)

(3) Hepatitis B and C Viruses (B형 및 C형 간염 바이러스)hepatocellular carcinoma ( = hepatoma)

(4) HHV8Kaposi sarcoma (mostly in AIDS patients)

6162 10. Chemical Carcinogenesis (화학적 발암)

A curious paradox existed for many years: many compounds known to be potent carcinogens are relatively inert in terms of chemical reactivityThe answer is that most chemical carcinogens require metabolic activation before they can react with cell constituents.

A mutagen is an agent that can permanently alter the genetic constitution of a cellAbout 90% of known carcinogens are mutagenic in a variety of in vitro systems.

Mutagenicity vs. Carcinogenicity63 10.2 Chemical Carcinogenesis is a Multistep Process (화학적 발암은 다단계의 과정이다)

1. Initiation (개시): a mutation in a single cell.

2. Promotion (촉진): the clonal expansion of the initiated cell. During promotion, the altered cells remain dependent on the continued presence of the promoting stimulus. This stimulus may be an exogenous chemical or physical agent or may reflect an endogenous mechanism (e.g., hormonal

1. Initiation (개시): a mutation in a single cell.

2. Promotion (촉진): the clonal expansion of the initiated cell. During promotion, the altered cells remain dependent on the continued presence of the promoting stimulus. This stimulus may be an exogenous chemical or physical agent or may reflect an endogenous mechanism (e.g., hormonal stimulation in the breast and prostate).

3. Progression (진행): autonomous growing (i.e., independent of the carcinogen or the promoter).

4. Cancer (암)64 10.3 Chemical Carcinogens Usually Undergo Metabolic Activation

(화학 발암제는 대체로 대사 활성화를 겪는다)About 75 chemicals are recognized as human carcinogens: most organic carcinogens, however, require conversion to an ultimate, more reactive compound.

다환 방향족 탄화수소 (polycyclic aromatic hydrocarbons): Found in cigarette smoke알킬화제 (alkylating agents): e.g. cyclophosphamide, cisplatin..아플라톡신 (aflatoxin): a natural product of the fungus Aspergillus flavus, found in contaminated peanuts and grains → liver cancer → ↑asia because grains?방향성 아민과 아조 염료 (aromatic amines and azo dyes)니트로사민 (nitrosamines)금속류(metals): Ni2+, Pb2+. Cd2+, Co2+, Be2+

65 11. Physical carcinogenesis (물리적 발암)11.1 UV Radiation Causes Skin Cancers

Cancers attributed to sun exposure, namely, basal cell carcinoma, squamous carcinoma, and melanoma occur predominantly in the white population.a carcinogenic effect occurs at wavelengths between 290 and 320 nm.the formation of pyrimidine dimers in DNA, a type of DNA damage that is not seen with any other carcinogen.Xeroderma pigmentosum (건피색소증), an autosomal recessive disease, ↑ [basal cell carcinoma, squamous carcinoma, melanoma]: Xero- (dry) + derma (skin) + pigmentosum (pigmented, stained)

66 11.2 Asbestos Causes Mesothelioma (석면은 중피종을 유발한다)Asbestos (석면)The characteristic tumor associated with asbestos exposure is malignant mesothelioma 악성중피종 of the pleural and

Asbestos (석면)The characteristic tumor associated with asbestos exposure is malignant mesothelioma 악성중피종 of the pleural and peritoneal cavities.

rare in the general population, has been reported to occur in 2% to 3% of heavily exposed workers.The latent period is usually about 20 years (or more).

67 12. Tumor Immunology: Immunologic Defenses Against Cancer in Animals and Humans (종양 면역학: 동물과 사람에서 암에 대한 면역 방어)Does immune defense work against cancer cell?→ it is clear from animal experiments that immune defenses against malignant tumors exist.

If the transplanted tumor is removed before it metastasizes (i.e., the mouse is cured of its tumor), reinjection of the tumor cells back into the cured mouse will not produce a tumor (although the cells remain capable of forming a tumor in a second naive mouse). → the transplanted tumor is rejected because of immunity acquired as a result of the initial tumor transplant.

An important observation is that tumors induced by the same chemical in different mice are antigenically distinct, whereas those induced by the same virus express the same virally determined antigens.

68 12.1 Tumor Antigens are Potential Targets for the Immune Response (종양 항원은 면역 반응의 잠재적 표적이다)It is much more difficult to document the presence of tumor-specific antigens 종양-특이 항원 in human cancers because of technical and ethical limitations.

Virally encoded antigens (e.g., HPV) → an anti-HPV vaccine is now used to prevent the development of cancer of the uterine cervix.

tumor-associated antigens 종양-관련 항원: small amounts in the adult but are abundant during development. → useful in clinical diagnosis and monitoring (CEA, Serum α-fetoprotein)

69 12.2 Mechanisms of Immunologic Response to Tumors (종양에 대한 면역학적 반응기전)1) T-cell-mediated cytotoxicity: lymphocytes from tumor-bearing hosts can transfer tumor immunity when injected into healthy animals. → the transferred immunity is eliminated by the administration of antibodies directed against T-cell antigens.2) Natural killer (NK) cell-mediated cytotoxicity: NK cell activated by IL-2 → can kill tumor: lymphokine-activated NK cell3) Macrophage-mediated cytotoxicity4) Antibody-dependent cell-mediated cytotoxicity5) Complement-mediated cytotoxicity

4) Antibody-dependent cell-mediated cytotoxicity5) Complement-mediated cytotoxicity

70 12.3 Evasion of Immunologic Responses by Tumors (종양에 의한 면역 회피)The fact that cancer is alive and well despite the presence of potential immunologic defenses implies that such mechanisms are either ineffective or that tumor cells can evade immunologic destruction.

Absence or paucity of tumor-specific antigens on the neoplastic cell Absence or paucity of cell surface molecules necessary for antigenic recognition (such as HLA) on the tumor cell Tumor heterogeneity leading to the selection of resistant tumor clones Expression of immunosuppressive molecules by tumor cells

71 13. Systemic Effects of Cancer on the Host (숙주에 대한 암의 전신효과)Paraneoplastic syndrome 신생물딸림 증후군, 부종양 증후군: remote effects that are not attributable to tumor invasion or to metastasis but may be related to the synthesis of bioactive compounds by the tumor.

fever: ① 종양의 성장과 관련 ② 치료 후 사라짐 ③ 재발 시 다시 나타남anorexia (식욕 부진), weight loss (체중 감소), cachexia (악액질)endocrine syndromes 내분비 증후군: malignant tumors may produce a number of peptide hormones with secretion that is not under normal regulatory control.

72 cachexia73 14. Organ-Specific Effects of Cancer on the Host

(숙주에 대한 암의 기관특이적 효과)14.1 Neurologic Syndromes are Common in Cancer Patients (신경학적 증후군은 암 환자에 흔하다)Neurologic disorders usually result from metastases or from endocrine or electrolyte disturbances.However, a small group of cancer patients suffer from a variety of neurologic complaints without any demonstrable

Most of these cases reflect an autoimmune etiology mediated by circulating antibodies directed against neural antigens or by reactive T cells.

74 14. Organ-Specific Effects of Cancer on theHost (숙주에 대한 암의 기관특이적 효과)14.2 Skeletal Muscle Syndromes (골격근 증후군) Can be Strongly Associated with Cancer

14.2 Skeletal Muscle Syndromes (골격근 증후군) Can be Strongly Associated with CancerPatients with dermatomyositis (피부근염) or polymyositis (다발성근염) have an incidence of cancer five to seven times higher than that in the general population.

14.3 Hematologic Syndromes (혈액학적 증후군) Commonly Relate to Marrow InfiltrationMost hematologic complication result from direct bone marrow infiltration of the marrow or from treatment.

75 14. Organ-Specific Effects of Cancer on theHost (숙주에 대한 암의 기관특이적 효과)14.4 Hypercoagulable State (혈액과응고 상태) is Often Associated with Cancer

The association between cancer and venous thrombosis was noted more than a century ago.Venous thrombosis (정맥혈전증): 50-fold risk of carcinoma of the pancreasDisseminated intravascular coagulation (파종성 혈관 내 응고): most commonly found with acute promyelocytic leukemia 급성전골수구 백혈병 and adenocarcinomas 샘암.Nonbacterial thrombotic endocarditis (비세균성 혈전성 심내막염): most common with solid tumors

76 14. Organ-Specific Effects of Cancer on theHost (숙주에 대한 암의 기관특이적 효과)14.5 Cancer also Affects a Number of Other Organ Systems

GASTROINTESTINAL SYSTEM:most cancer patients develop malabsorption 흡수장애, histologic abnormalities of the small intestine, even though the tumor may not directly involve the bowel.KIDNEY: Nephrotic syndrome (신증후군), as a consequence of renal vein thrombosis (신정맥혈전증) or amyloidosis (아밀로이드증) is a well-known complication of cancerSKIN: pigmented lesions (착색병변) and keratoses (각화증): more than half of patients with acanthosis nigricans (흑색 극세포증), a disorder with hyperkeratosis and pigmentation of the axilla, neck, flexures, and anogenital region, have cancer.

14.6 Amyloidosis May be a Systemic Effect of Cancer → Chapter 2377 15. Epidemiology of Cancer (암의 역학)

Significant differences of incidence in different ethnic groups or geographical regions.Liver cancer: sub-Saharan Africa and most of Asia, Indonesia, and the Philippines.Skin cancer

Liver cancer: sub-Saharan Africa and most of Asia, Indonesia, and the Philippines.Skin cancer: northern Australia (↑ sun exposure, ↑white vs. ↓aboriginal): ↓↓ Asian: ↓ Black (melanoma in palms & soles)Cervical carcinoma: Jews (↓) vs. Hispanic (↑)Burkitt lymphoma: Uganda (↑), Malaysia (↑) vs. Europe, America (↓)

7879 15.2 Studies of Migrant Populations Give Clues to Cancer Development

(이민 인구집단에서의 연구는 암 발생의 단서를 제공한다)