Biology of Cancer Biology of Cancer

Pathophysiology of CancerPathophysiology of Cancer

Raul H. Morales-Borges, M.D., FICPS, FIACATHRaul H. Morales-Borges, M.D., FICPS, FIACATH

Ashford Institute of Hematology & OncologyAshford Institute of Hematology & Oncology

IntroductionIntroduction

Cancer is a leading cause of death and Cancer is a leading cause of death and source of morbidity of adults in the source of morbidity of adults in the Western world.Western world.

There are many causes including There are many causes including environment, heredity, and behavior environment, heredity, and behavior interactions.interactions.

IntroductionIntroduction

All malignant cells arise from a All malignant cells arise from a transformation of a normal cell into transformation of a normal cell into an immortal cell which growth an immortal cell which growth uncontrolled.uncontrolled.

Such transformation occurs when the Such transformation occurs when the genetic blueprint - the cell’s DNA - is genetic blueprint - the cell’s DNA - is damaged or altered.damaged or altered.

Every cell contain a series of genetic Every cell contain a series of genetic markers known as markers known as protooncogenes.protooncogenes.

IntroductionIntroduction

Tumor development is a multistep Tumor development is a multistep process.process.

Molecular research is providing interesting Molecular research is providing interesting new modalities of treatments.new modalities of treatments.

Management is multidisciplinary.Management is multidisciplinary.

Our goals should be prevention, early Our goals should be prevention, early detection, and provide good quality of life. detection, and provide good quality of life.

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Cancer Cancer

Cancer = Karkinoma, Crab (Cangrejo)Cancer = Karkinoma, Crab (Cangrejo)

Neoplasm = New Growth (Crecimiento Neoplasm = New Growth (Crecimiento Nuevo)Nuevo)

Oncos = TumorOncos = Tumor

Definition from 1922Definition from 1922

It is a tissue overgrowth It is a tissue overgrowth independently from the governing independently from the governing laws of the body. laws of the body.

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Caracteristicas de Tumor BenignoCaracteristicas de Tumor Benigno

Crecimiento lentoCrecimiento lento

Son bien diferenciadosSon bien diferenciados

Tienen una capsula bien definidaTienen una capsula bien definida

No invasion a otros tejidosNo invasion a otros tejidos

No metastasisNo metastasis

Ejemplos de tumores benignosEjemplos de tumores benignos

PapilomaPapiloma

AdenomaAdenoma

CystadenomaCystadenoma

NevusNevus

NeurofibromaNeurofibroma

LipomaLipoma

HemangiomaHemangioma

LinfangiomaLinfangioma

Fibromatosis Fibromatosis (desmoide)(desmoide)

OsteomaOsteoma

CondromaCondroma

LeiomiomaLeiomioma

RhabdomiomaRhabdomioma

MeningiomaMeningioma

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Caracteristicas de Tumor MalignoCaracteristicas de Tumor Maligno

Proliferacion de celulas neoplasticas Proliferacion de celulas neoplasticas No encapsuladosNo encapsuladosPierden la diferenciacionPierden la diferenciacionEstroma de soporteEstroma de soporteNeovascularizacion (vasos sanguineo Neovascularizacion (vasos sanguineo nuevos)nuevos)Invasion y MetastasisInvasion y Metastasis

Ejemplos de tumores malignosEjemplos de tumores malignos

CarcinomaCarcinoma

AdenocarcinomaAdenocarcinoma

MelanomaMelanoma

SeminomaSeminoma

MielomaMieloma

LinfomaLinfoma

LeucemiasLeucemias

CondrosarcomaCondrosarcoma

NeuroblastomaNeuroblastoma

RetinoblastomaRetinoblastoma

Tumor de WilmTumor de Wilm

Tumor de EwingTumor de Ewing

MesoteliomaMesotelioma

SarcomaSarcoma

FibrosarcomaFibrosarcoma

AngiosarcomaAngiosarcoma

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Estadios de Tumores malignosEstadios de Tumores malignos

Depende del tamano del tumor, nodulos Depende del tamano del tumor, nodulos linfaticos y metastasislinfaticos y metastasis

Estadio I – pequenoEstadio I – pequeno

Estadio II – algo mas grande, algunos Estadio II – algo mas grande, algunos nodulosnodulos

Estadio III – invasion de estructuras vecinas, Estadio III – invasion de estructuras vecinas, mas nodulosmas nodulos

Estadio IV - metastasisEstadio IV - metastasis

Carcinoma in situ (CIS)Carcinoma in situ (CIS)

Pre-invasive epithelial malignant tumors of Pre-invasive epithelial malignant tumors of glandular or squamous cell origin.glandular or squamous cell origin.

Localized to the epithelium.Localized to the epithelium.

No broken local basement membrane.No broken local basement membrane.

No invasion of surrounded tissues.No invasion of surrounded tissues.

Seen in the cervix, beast, skin, oral cavity, Seen in the cervix, beast, skin, oral cavity, esophagus, stomach, bronchus.esophagus, stomach, bronchus.

Cancer Cells: Cancer Cells: TransformationTransformation

TransformationTransformation means the process by means the process by which a cell becomes cancerous.which a cell becomes cancerous.AutonomyAutonomy is when the cancer cell is is when the cancer cell is independently from normal cellular independently from normal cellular controls. Cancerous cells show controls. Cancerous cells show uninhibited uninhibited growth. growth. They are often They are often anchorage-independent anchorage-independent (they divide even in a soft agar gel).(they divide even in a soft agar gel).They are usually They are usually immortal. immortal.

Cancer Cells:Cancer Cells:DifferentiationDifferentiation

Differentiation Differentiation refers to the process of refers to the process of acquiring a specialized function and acquiring a specialized function and organization.organization.AnaplasiaAnaplasia is the absence of differentiation. is the absence of differentiation. It is recognized by a loss of organization It is recognized by a loss of organization and a marked increase in nuclear size, and a marked increase in nuclear size, with evidence of ongoing proliferation. The with evidence of ongoing proliferation. The cells are of variable size and shape cells are of variable size and shape ((pleomorphismpleomorphism).).

Cancer Stem CellsCancer Stem Cells

Two characteristics: Self-renew & Two characteristics: Self-renew & Multipotent.Multipotent.

When a stem cell divides, each daughter When a stem cell divides, each daughter cell has a choice:cell has a choice:– It can either continue as a stem cell or go on It can either continue as a stem cell or go on

to become terminally differentiated, that is, to become terminally differentiated, that is, completely matured (e.g., neuron, myocyte, completely matured (e.g., neuron, myocyte, erythrocyte).erythrocyte).

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Grado de TumoresGrado de Tumores

Grado I – Bien diferenciadosGrado I – Bien diferenciados

Grado II – Moderadamente Grado II – Moderadamente diferenciadosdiferenciados

Grado III – Pobremente diferenciadosGrado III – Pobremente diferenciados

Grado IV - AnaplasticosGrado IV - Anaplasticos

The Genetic Basis of CancerThe Genetic Basis of Cancer

Clonal selectionClonal selection: Cancer is a disease of : Cancer is a disease of aging because the cells acquires a aging because the cells acquires a number of genetic mutations over time and number of genetic mutations over time and the cells then may have a selective the cells then may have a selective advantage over its mutant neighbors advantage over its mutant neighbors ((Clonal proliferation or clonal expansionClonal proliferation or clonal expansion). ).

Malignant Cell Proliferation

Carcinogenesis

Molecular abnormalities in lung cancer

Commonly observedgenetic changes

Tobaccocarcinogen

Inappropriate response to external signals

Loss of cell cycle controlLoss of apoptosis pathwayLoss of contact inhibition

Ability to metastasiseAngiogenesis

ImmortalityAutocrine growth loops

Atypical alveolarhyperplasia

Premalignantadenomas

Lung cancer

Carcinoma in situ

DysplasiaBronchial

metaplasia

Normal epithelium

Sequential changes during lung cancer pathogenesisEarly Intermediate Late

Normal epithelium

Hyperplasia Dysplasia CIS Invasive carcinoma

~80%3p LOH/small telomeric deletions 3p LOH/contiguous deletions

~50%Microsatellite alterations

~70%9p21 LOH

~80%Telomerase dysregulation Telomerase upregulation

~60%myc overexpression

~80%8p21-23 LOH

~40%Neoangiogenesis

~40%Loss of Fhit immunostaining

~70%p53 LOH p53 mutations

~80%Aneuploidy

~100%Methylation

~30%5q21 APC-MCC LOH

~20%K-ras mutation

Hirsch et al 2001LOH, loss of heterozygosity

Oncogenes and Tumor-suppressor Oncogenes and Tumor-suppressor genesgenes

Oncogenes are mutant genes that in their Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of normal nonmutant state direct synthesis of proteins that positively regulate proteins that positively regulate proliferation.proliferation.

Tumor-suppressor genes encode proteins Tumor-suppressor genes encode proteins that in their normal state negatively that in their normal state negatively regulate proliferation.regulate proliferation.

It’s an oncogene in a normal, nonmutant It’s an oncogene in a normal, nonmutant state.state.

The protooncogenes serve to many basic The protooncogenes serve to many basic functions to the normal cell such as: growth, functions to the normal cell such as: growth, maturation and proliferationmaturation and proliferation

However, such protooncogenes can be However, such protooncogenes can be altered and become Oncogenesaltered and become Oncogenes

Such Oncogenes confers certain Such Oncogenes confers certain characteristic to the cell : characteristic to the cell : uncontrolled uncontrolled growth, invasiveness and immortalitygrowth, invasiveness and immortality

PROTOONCOGENESPROTOONCOGENES

How does the change from How does the change from protooncogenes to Oncogenes occur?protooncogenes to Oncogenes occur?

There are several There are several stepssteps toward the toward the malignant transformation of a cellmalignant transformation of a cell– Non-lethal genetic damage lies at the heart Non-lethal genetic damage lies at the heart

of of carcinogenesiscarcinogenesisA genetic damage (A genetic damage (mutationmutation) may be acquired by ) may be acquired by the action of environmental agents such as the action of environmental agents such as chemicals, radiation or viruses, or it may be chemicals, radiation or viruses, or it may be inheritedinherited

– Two classes of normal regulatory genes - the Two classes of normal regulatory genes - the growth promoting protooncogenes and the growth promoting protooncogenes and the growth inhibiting genes (growth inhibiting genes (antioncogenesantioncogenes) - are ) - are the principal targets of genetic damagethe principal targets of genetic damage

– Carcinogenesis is a multistep processCarcinogenesis is a multistep process at at both the phenotypic and genetic levelboth the phenotypic and genetic level

– Every human cancer that has been analyzed Every human cancer that has been analyzed reveals multiple genetic alterations involving reveals multiple genetic alterations involving activation of several Oncogenes and activation of several Oncogenes and inactivation of two or more antioncogenesinactivation of two or more antioncogenes

The genetic damage that activates The genetic damage that activates Oncogenes may be subtle or large Oncogenes may be subtle or large enough to be detected in a gross enough to be detected in a gross chromosomal analysis: a karyotype chromosomal analysis: a karyotype analysis.analysis.

In some cancers such alterations are In some cancers such alterations are nonrandom and commonnonrandom and common

Specific alterations have been identified Specific alterations have been identified for most leukemia's and lymphomasfor most leukemia's and lymphomas

The most common types of such The most common types of such alterations are:alterations are:

– translocationstranslocations

– deletionsdeletions

– gene amplificationgene amplification

– point mutationspoint mutations

Point MutationsPoint Mutations

They are the most common events in They are the most common events in small scale changes in DNA.small scale changes in DNA.

It’s an alteration of one or a few nucleotide It’s an alteration of one or a few nucleotide base pairs.base pairs.

e.g., e.g., ras generas gene is associated with is associated with pancreatic and colorectal cancer. pancreatic and colorectal cancer.

Chromosome TranslocationChromosome Translocation

It can cause excess and inappropriate It can cause excess and inappropriate production of a proliferation factor (e.g., production of a proliferation factor (e.g., t(8;14) in Burkitt lymphomas) such as t(8;14) in Burkitt lymphomas) such as MYC protein.MYC protein.

It can also lead to production of novel It can also lead to production of novel proteins with growth promoting properties proteins with growth promoting properties (e.g., t(9;22) in CML) such as BCR-ABL (e.g., t(9;22) in CML) such as BCR-ABL protein. protein.

Gene AmplificationGene Amplification

Result of duplication of a small piece of a Result of duplication of a small piece of a chromosome over and over again, so that chromosome over and over again, so that instead of normal two copies of a gene, tens or instead of normal two copies of a gene, tens or even hundreds of copies are present.even hundreds of copies are present.

Results in increased expression of an oncogene, Results in increased expression of an oncogene, or in some cases, drug resistance genes.or in some cases, drug resistance genes.

E.g.: N-myc in Neuroblastoma & erb2 in Breast E.g.: N-myc in Neuroblastoma & erb2 in Breast cancer.cancer.

Tumor-Suppressor genes Tumor-Suppressor genes

They are genes whose major function is to They are genes whose major function is to negatively regulate cell growth and prevent negatively regulate cell growth and prevent mutations.mutations.Needs two (2) mutational events to contribute to Needs two (2) mutational events to contribute to the cancer.the cancer.Loss of function, acts in recessive fashion.Loss of function, acts in recessive fashion.Inherited form is common and has a tissue Inherited form is common and has a tissue preference.preference.Examples: p53 (GBM, SCLC, BCA, CRC), Rb Examples: p53 (GBM, SCLC, BCA, CRC), Rb (retinoblastoma), APC & MCC (CRC).(retinoblastoma), APC & MCC (CRC).

Loss of heterozygosityLoss of heterozygosity

Loss of a chromosome region in a tumor.Loss of a chromosome region in a tumor.

Unmasks inactivating mutations in Unmasks inactivating mutations in recessive tumor suppression genes.recessive tumor suppression genes.

Also named as allelic loss.Also named as allelic loss.

Examples: LOH for 5q for sporadic Examples: LOH for 5q for sporadic adenomas to carcinomas, Loss of the adenomas to carcinomas, Loss of the 13q14 chromosome region on one 13q14 chromosome region on one chromosome for Rb.chromosome for Rb.

Gene SilencingGene Silencing

The epigenetic silencing is associated with The epigenetic silencing is associated with methylation of both the DNA and methylation of both the DNA and associated chromatin. So, no functional associated chromatin. So, no functional protein will be produced.protein will be produced.

Holistic scheme of multistage carcinogenesis Holistic scheme of multistage carcinogenesis with 3 types of control systemswith 3 types of control systems

Agonist induced signal transduction

Cell cycle controlFidelity of DNA

and Chromosome replication

In the near past, our understanding of In the near past, our understanding of cellular function was rudimentarycellular function was rudimentaryNow, our knowledge of cells has Now, our knowledge of cells has progressed to an understanding of many progressed to an understanding of many complex interactions and networks:complex interactions and networks:– extracellularextracellular– intracellularintracellular– intranuclearintranuclear

The genome project has amplified this The genome project has amplified this capacity through numerous techniques, capacity through numerous techniques, including the cluster array analysisincluding the cluster array analysisBreast cancer cells are now classified in five Breast cancer cells are now classified in five groupsgroups– basal likebasal like - null cell- null cell– erb2+ A & Berb2+ A & B– normalnormal

Alterations in progrowth and Alterations in progrowth and antigrowthantigrowth

Cancer cells have mutations that enable them to Cancer cells have mutations that enable them to proliferate in the absence of external growth proliferate in the absence of external growth signals. To achieve this, some caner cells acquire signals. To achieve this, some caner cells acquire the ability to secrete growth factors that stimulate the ability to secrete growth factors that stimulate their own growth (their own growth (Autocrine stimulation).Autocrine stimulation). Other have an Other have an increase in growth factor receptorsincrease in growth factor receptors (EGFR), an (EGFR), an activating mutation in an intracellular activating mutation in an intracellular signaling proteinsignaling protein called called ras, an antigrowth ras, an antigrowth signaling signaling such as such as Rb,Rb, and and a self-destruction a self-destruction mechanism mechanism such as such as apoptosis (p53). apoptosis (p53).

AngiogenesisAngiogenesis

Neovascularization is a characteristic of Neovascularization is a characteristic of cancer cells to provide their own new cancer cells to provide their own new vessel supply. It’s secondary to purified vessel supply. It’s secondary to purified angiogenic factors such as bFGF & angiogenic factors such as bFGF & VEGF.VEGF.Vascular endothelial growth factor is Vascular endothelial growth factor is angiogenic in vivo for endothelial cells.angiogenic in vivo for endothelial cells.Basic fibroblast growth factor is mitogenic Basic fibroblast growth factor is mitogenic for vascular endothelial cells and is for vascular endothelial cells and is strongly angiogenic.strongly angiogenic.

Model of role of angiogenesis in Model of role of angiogenesis in metastasismetastasis

Angiogenesis

Expansion of Tumor cells

Microinvasion

Enter & Exit Circulation

Limited growth in Target Organ

Angiogenesis

Expansion into detectable metastasis

TelomeresTelomeres

They are protective ends, or caps, on each They are protective ends, or caps, on each chromosome and are placed and maintained by chromosome and are placed and maintained by a specialized enzyme called a specialized enzyme called telomerasetelomerase. . Telomerase is usually active only in germ cells in Telomerase is usually active only in germ cells in ovaries and testes and in stem cells. ovaries and testes and in stem cells. When the telomeres become critically small, the When the telomeres become critically small, the chromosomes become unstable and fragment, chromosomes become unstable and fragment, then the cells die. Cancer cells at critical activate then the cells die. Cancer cells at critical activate telomerase to restore and maintain their telomerase to restore and maintain their telomere to survive and divide. telomere to survive and divide.

Cyclin E*

Cell cycle and therapeutic targetsDNA

damageor oxygen

deprivation

Cell suicide(apoptosis)p53*

p21

InactivepRB

protein

External signal that inhibits cell

division

TGF

Rb + E2F

Early G1 Late G1S G2

M

Phases of cell cycle

p15* p16*

p27

green Activity that promotes cell division

pink Activity that discourages cell division

* Mutation or deregulation of gene for this protein hasbeen found in human tumours

R

External signal that

promotes cell

division Cyclin E-CDK2

complex

Proteins involved in

DNAsynthesisCDK2

DNAsynthesis

Celldivision

Cyclin B-CDK1

complex

Cyclin A

CDK1

Cyclin BCyclin A-

CDK1complex

Liberatedtranscription

factors

Cyclin D-CDK4/6complex

CDK4/6

Cyclin D*

Prognostic and predictive factorsPrognostic and predictive factorsp53 statusp53 status

Other cell cycle components including p27, p15, p16, pRb, cyclin Other cell cycle components including p27, p15, p16, pRb, cyclin and CDK and CDK

K-ras mutationsK-ras mutations

HER2/neu and epidermal growth factor receptor (EGFR)HER2/neu and epidermal growth factor receptor (EGFR)

Beta tubulinBeta tubulin

Expression of matrix metalloproteinase and inhibitorsExpression of matrix metalloproteinase and inhibitors

DNA topoisomerase IIDNA topoisomerase II and II and II

Single nucleotide polymorphism in myeloperoxidase gene Single nucleotide polymorphism in myeloperoxidase gene reduces risk of lung cancerreduces risk of lung cancer

Heparin-binding growth factor pleiotrophinHeparin-binding growth factor pleiotrophin

Strategies for signalling inhibition

Tyrosine kinase inhibitors (TKIs)

Immuneeffector cell

Anti-ligand mAbs

BispecificAbs

Anti-receptormAbs

Ligand/toxin conjugate

scFv/toxinconjugates

Ligand-genisteinconjugates

IntracellularscFvs

Nucleus

Antisense

Inhibitors of other signalling molecules

DNA

Mode of action of EGFR inhibitors

Membrane

Extracellular

Intracellular

R

K

R

K EGFR-TKIEGFR-TKI Signalling

Proliferation Cell survival (anti-apoptosis)

Growth factors

Chemotherapy/radiotherapy sensitivity

Angiogenesis

Metastasis

R, epidermal growth factor receptor

EGF/TGFα

Antibody

Human Cancer & Family Genetics Human Cancer & Family Genetics

Germline mutations.Germline mutations.

Inheritance of a mutated gene that can Inheritance of a mutated gene that can cause cancer.cause cancer.

Examples: Neuroblastoma, Wilm’s tumor, Examples: Neuroblastoma, Wilm’s tumor, Neurofibromatosis, Breast Cancer, Neurofibromatosis, Breast Cancer, Familial Polyposis coli or Adenomas of the Familial Polyposis coli or Adenomas of the colon.colon.

Causas HereditariasCausas Hereditarias

Neurofibromatosis (Enfermedad de von Neurofibromatosis (Enfermedad de von Reckinghausen) : Neurofibro-sarcomasReckinghausen) : Neurofibro-sarcomas

Sindrome de Gardner : Fibro-sarcomas desmoides del Sindrome de Gardner : Fibro-sarcomas desmoides del mesenteriomesenterio

Retinoblastoma familiar : Osteo-sarcomasRetinoblastoma familiar : Osteo-sarcomas

Sindrome Familiar de Li-Fraumeni Sindrome Familiar de Li-Fraumeni

Sindrome de Stewart-Treves -AngiosarcomasSindrome de Stewart-Treves -Angiosarcomas

Hemocromatosis Hemocromatosis

4848

Causas Geneticas de SarcomasCausas Geneticas de Sarcomas

Translocaciones: t(11;22), t(12;14), Translocaciones: t(11;22), t(12;14), t(2;13), t(X;18), t(12;16)t(2;13), t(X;18), t(12;16)

Expesion de MDR 1Expesion de MDR 1

Mutaciones: genes p53, Rb Mutaciones: genes p53, Rb

Deleciones: 1p-, 3p-, 13q-Deleciones: 1p-, 3p-, 13q-

Proto-oncogenes: c-myc, N-myc, c-myb, Proto-oncogenes: c-myc, N-myc, c-myb, c-mil/raf-1, c-fes, c-sisc-mil/raf-1, c-fes, c-sis

Pathologe 17(3):195-201, 1996 Diagnostic Molecular Pathology 5(2):98-106, 1996

Monographs in Pathology 38:65-128, 1996 American J of Pathology 150(6):1997-2007, 1997

Seminars in Oncology 24(5):515-525, 1997 J Cancer Research & Clinical Oncology 123(4):211-8, 1997

Inflammatory Conditions & Inflammatory Conditions & CancerCancer

Reactive Oxygen Species

Increased COX2

Proliferation

Release of growth factors

Release of cytokines

Injury

Cancer

Chronic Inflammation & CancerChronic Inflammation & Cancer

Chronic Ulcerative Colitis : Colon CancerChronic Ulcerative Colitis : Colon Cancer

Chronic Hepatitis B or Hepatitis C : Liver CancerChronic Hepatitis B or Hepatitis C : Liver Cancer

COPD, Chronic asthma : Lung CancerCOPD, Chronic asthma : Lung Cancer

Chronic Cystitis : Bladder CancerChronic Cystitis : Bladder Cancer

Sjogren syndrome : LymphomaSjogren syndrome : Lymphoma

Chronic Thyroiditis : Lymphoma Chronic Thyroiditis : Lymphoma

Fibrocystic Breast Disease : Breast CancerFibrocystic Breast Disease : Breast Cancer

Benign Prostate Hyperplasia : Prostate CancerBenign Prostate Hyperplasia : Prostate Cancer

Histopathological Appearance of Benign Breast Disease (Hematoxylin and Eosin)

Hartmann, L. et al. N Engl J Med 2005;353:229-237

BENIGN BREAST DISEASES

(FIBROCYSTIC BREAST DISEASE)

Benign Breast Disease Benign Breast Disease may not be so benignmay not be so benign

From Mayo Clinic Cancer CenterFrom Mayo Clinic Cancer Center

If developed before 40 y/o the risk of BCA If developed before 40 y/o the risk of BCA can increase by can increase by 83%83% and if we add a and if we add a strong family history the risk increases by strong family history the risk increases by 93%.93%.

Viral Infections & CancerViral Infections & Cancer

Ellerman in Denmark in 1908 and Rous in 1911: Ellerman in Denmark in 1908 and Rous in 1911: Retrovirus and Avian leukemia & Avian sarcoma. Retrovirus and Avian leukemia & Avian sarcoma. Hepatitis B & C viruses – Hepatocellular carcinomaHepatitis B & C viruses – Hepatocellular carcinomaHerpes virus / Epstein-Barr – Burkitt lymphoma, Herpes virus / Epstein-Barr – Burkitt lymphoma, nasopharyngeal carcinomanasopharyngeal carcinomaKSHV / HHV-8 – Kaposi sarcomaKSHV / HHV-8 – Kaposi sarcomaHPV – Cervical and anogenital carcinomaHPV – Cervical and anogenital carcinomaRetrovirus Retrovirus – HTLV-1 – Adult-T-cell leukemia/lymphomaHTLV-1 – Adult-T-cell leukemia/lymphoma– HTLV-2 – Hairy- cell leukemia HTLV-2 – Hairy- cell leukemia – HIV – Kaposi sarcoma HIV – Kaposi sarcoma

HEAD & NECK CANCERHEAD & NECK CANCERNasopharyngeal cancer Nasopharyngeal cancer and Epstein-Barr virusand Epstein-Barr virus

Endemic in regions of Northern Africa and Endemic in regions of Northern Africa and AsiaAsia

Etiology distinct from other head and Etiology distinct from other head and neck cancers neck cancers

Epstein-Barr viral proteins detectable Epstein-Barr viral proteins detectable in majority of nasopharyngeal tumorsin majority of nasopharyngeal tumors

Associated with frequent consumption Associated with frequent consumption of salted fish or nitrosaminesof salted fish or nitrosamines

Stupp R, Vokes EE. Current Cancer Therapeutics. 3rd ed. 1998;165-166.

HPVHPV>100 types identified2

30–40 anogenital2,3

– 15–20 oncogenic*,2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584

HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers.5

– Nononcogenic† types include: 6, 11, 40, 42, 43, 44, 544

HPV 6 and 11 are most often associated with external genital warts.3

1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105.

Nonenveloped double-stranded DNA virus1

*High risk; †Low risk

1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224.

Discovery of the Link Between Discovery of the Link Between HPV and Cervical CancerHPV and Cervical Cancer

Body of information developed slowly based on advances Body of information developed slowly based on advances in cellular, molecular, and immunological diagnostic in cellular, molecular, and immunological diagnostic technologies over the past 20 yearstechnologies over the past 20 years11

Epidemiological case-control

studies completed1

HPV defined as large, closely

related family1: >100 types2;

30–40 anogenital2,3

HPV genomes found in cervical

carcinomas1

HPV viruses cloned1

Mechanisms of transformation

elucidated (true “tumor virus”)1

15–20 HPV types classified as oncogenic2,3

Link Between HPV and Cervical Link Between HPV and Cervical CancerCancer

99% of Cervical cancers and High-grade 99% of Cervical cancers and High-grade cervical cancer precursor lesions cervical cancer precursor lesions associated with HPVassociated with HPV

Risk for developing cervical cancer with Risk for developing cervical cancer with HPV is 50-100x higher than without HPV HPV is 50-100x higher than without HPV infectioninfection

Risk of High-grade precursor lesion with Risk of High-grade precursor lesion with HPV is 300-foldHPV is 300-fold

Bacterial – Parasitic Infection & Cancer Bacterial – Parasitic Infection & Cancer

Helicobacter pylori – Gastric cancer, Helicobacter pylori – Gastric cancer, MALTMALT

Opisthorchis viverrini – Cholangio-Opisthorchis viverrini – Cholangio-carcinomacarcinoma

Schistosoma haematobium – Bladder Schistosoma haematobium – Bladder carcinomacarcinoma

Environmental Factors & CancerEnvironmental Factors & Cancer

Carcinogens are agents Carcinogens are agents that can cause cancer.that can cause cancer.

Xenobiotics are toxic, Xenobiotics are toxic, mutagenic, and mutagenic, and canrcinogenic chemicalscanrcinogenic chemicals

Important factors to be Important factors to be considered are: time of considered are: time of exposure, racial & gender exposure, racial & gender disparities, human disparities, human contamination & public contamination & public health advocacyhealth advocacy

Tobacco smoke has Tobacco smoke has polycyclic aromatic polycyclic aromatic hydrocarbons, nitroso hydrocarbons, nitroso compounds, compounds, arylamines, benzo(a) arylamines, benzo(a) pyrene metabolites, pyrene metabolites, and benzene which and benzene which are potent are potent carcinogens.carcinogens.

Causas de SarcomasCausas de Sarcomas

Exposicion a RadioterapiaExposicion a RadioterapiaPacientes inmunocomprometidosPacientes inmunocomprometidosExposicion a quimicos como hidro-carburos Exposicion a quimicos como hidro-carburos policiclicos, cloruro de polivinil, asbestos, dioxina policiclicos, cloruro de polivinil, asbestos, dioxina de los herbicidas.de los herbicidas.Cicatrices de cirugias previas, quemaduras, dano e Cicatrices de cirugias previas, quemaduras, dano e implantacion de cuerpo extranoimplantacion de cuerpo extranoHespes virus 8, HIV, HTLV-III, Rous Sarcoma virusHespes virus 8, HIV, HTLV-III, Rous Sarcoma virusTumores Benignos de huesos: condromas, displasia Tumores Benignos de huesos: condromas, displasia fibrosa, Enfermedad de Paget del huesofibrosa, Enfermedad de Paget del hueso

Tobacco & Related CancersTobacco & Related Cancers

LungLung

Oral cavity, pharynx, larynx, nasal cavity, Oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, esophagus & stomachparanasal sinuses, esophagus & stomach

Pancreas & LiverPancreas & Liver

Penis, kidney, bladderPenis, kidney, bladder

Cervix uteriCervix uteri

Myeloid leukemiaMyeloid leukemia

Radiation & CancerRadiation & Cancer

20 to 250 cGy for linear energy transfer 20 to 250 cGy for linear energy transfer radiation, such as x-rays or gamma-rays is radiation, such as x-rays or gamma-rays is the human cancer risk dose.the human cancer risk dose.

Radiation-induced gene mutations or Radiation-induced gene mutations or chromosomal abnormalities that can be chromosomal abnormalities that can be detected early (within 24 hours of radiation detected early (within 24 hours of radiation exposure) are not solely responsible for exposure) are not solely responsible for tumor development in normal human cells.tumor development in normal human cells.

Genomic instability & RadiationGenomic instability & Radiation

Mitotic failure

Cell death Chromosome alteration

Gene mutation

DNA damage

Ionizing radiation

Bystander effect

&

Gap Junction Intercellular Communication

Ultraviolet radiation & Skin CancerUltraviolet radiation & Skin Cancer

It causes melanoma, basal cell carcinoma and It causes melanoma, basal cell carcinoma and squamous cell carcinoma of the skin.squamous cell carcinoma of the skin.The degree of damage depends on the intensity The degree of damage depends on the intensity and wavelength content and the depth of and wavelength content and the depth of penetration.penetration.It induces release of tumor necrosis factor in the It induces release of tumor necrosis factor in the epidermis.epidermis.Inflammation is a critical component through Inflammation is a critical component through hydrogen peroxide.hydrogen peroxide.Activation of the mitogen-activated protein Activation of the mitogen-activated protein kinase (MAPK) (eg. Melanoma) kinase (MAPK) (eg. Melanoma)

Multistep skin CarcinogenesisMultistep skin Carcinogenesis

Protein oxidationLipid peroxidation

XenobioticsMutate

protooncogenes

Inflammation ROS

Direct DNADamage

UVR

OxidativeStress

Alcohol ConsumptionAlcohol Consumption

Associated with cancer of the: oral cavity, Associated with cancer of the: oral cavity, pharynx, hypopharynx, esophagus, liver, breast, pharynx, hypopharynx, esophagus, liver, breast, colorectum.colorectum.

Mechanisms: effect of acetaldehyde, induction of Mechanisms: effect of acetaldehyde, induction of cytochrome P-4502 E1 leading to the generation cytochrome P-4502 E1 leading to the generation of ROS, increased procarcinogen activation, of ROS, increased procarcinogen activation, modulation of cellular regeneration, nutritional modulation of cellular regeneration, nutritional deficiency, altered mucosal integrity, enzyme deficiency, altered mucosal integrity, enzyme and metabolic dysfunction, structural and metabolic dysfunction, structural abnormalities. abnormalities.

Physical ActivityPhysical Activity

Related with breast and colon cancers.Related with breast and colon cancers.Mechanisms: increases insulin and insulin-Mechanisms: increases insulin and insulin-like growth factors, obesity, decreasing like growth factors, obesity, decreasing free radical scavenger systems, free radical scavenger systems, inflammatory mediators, increasing inflammatory mediators, increasing estrogen and androgens, decreasing gut estrogen and androgens, decreasing gut motility.motility.Rx: for CRC we need 3.5 – 4 hours/week, Rx: for CRC we need 3.5 – 4 hours/week, for BCA we need 30 – 60 minutes /day. for BCA we need 30 – 60 minutes /day.

Diet & ObesityDiet & Obesity

Important risk factors: low fiber and high fat diet, Important risk factors: low fiber and high fat diet, obesity, alcohol consumption, contaminated obesity, alcohol consumption, contaminated corn, peanuts and rice with aflatoxin, Chinese-corn, peanuts and rice with aflatoxin, Chinese-style salted fish, hot beverages, grilled meat, red style salted fish, hot beverages, grilled meat, red or processed food.or processed food.

Overweight and obesity are linked with cancer Overweight and obesity are linked with cancer of: breast, colorectal, esophagus, gastric, liver, of: breast, colorectal, esophagus, gastric, liver, gallbladder, pancreas, prostate, uterine, cervix, gallbladder, pancreas, prostate, uterine, cervix, ovaries, non-Hodgkin’s lymphoma, multiple ovaries, non-Hodgkin’s lymphoma, multiple myeloma, leukemia. myeloma, leukemia.

Biologic mechanisms of obesity Biologic mechanisms of obesity and cancerand cancer

Free fatty acids, TNF,

Resistin

Increased bioavailability of

Insulin-like growth factor-1

Increased WEIGHTADIPOSITY

Insulin resistant

Decreased liver synthesis, blood, and tissue of insulin-like

growth factor binding protein 1 & 2

Decreased apoptosis & Increased Cell proliferation

Tumor development

Obesity, hormones, and cancerObesity, hormones, and cancer

Aromatase & 17-B-Hydroxy

Steroid Dehydrogenase

Diffusion into target organsDecreased apoptosis

Increased ProliferationLoss of differentiation

Adipose tissue

Increased bioavailability ofEstradiol & testosterone

Reduced levels ofSex Hormone Binding Globulin

Air PollutionAir Pollution

Indoor pollution is worse than outdoor Indoor pollution is worse than outdoor pollution.pollution.

Indoor pollutants:Indoor pollutants:– Environmental Tobacco SmokeEnvironmental Tobacco Smoke– Radon gas (lung cancer)Radon gas (lung cancer)– Inorganic Arsenic (bladder, skin, and lung Inorganic Arsenic (bladder, skin, and lung

cancers) cancers)

Electromagnetic fieldsElectromagnetic fields

It’s controversial, little evidence is It’s controversial, little evidence is available. Further research is needed.available. Further research is needed.

Some association: Leukemia in children & Some association: Leukemia in children & Brain Tumor in adults. Brain Tumor in adults.

EMR -> Thermal effect -> Protein EMR -> Thermal effect -> Protein phosphorylation (?)phosphorylation (?)

Occupational CarcinogensOccupational Carcinogens

Asbestos: mesothelioma, lung cancerAsbestos: mesothelioma, lung cancerChromium, Nickel, Mustard gas: : lung cancerChromium, Nickel, Mustard gas: : lung cancerHeterocyclic Amines: Colon Cancer Heterocyclic Amines: Colon Cancer Dyes, Rubber, Paint, and Aromatic amines: Dyes, Rubber, Paint, and Aromatic amines: Bladder cancerBladder cancerAflatoxin B, Vinyl chloride: Liver cancerAflatoxin B, Vinyl chloride: Liver cancerCadmium: Prostate cancer Cadmium: Prostate cancer Benzol inhalation & leukemia in shoemakers, Benzol inhalation & leukemia in shoemakers, rubber cement industry, explosives, and dyeing rubber cement industry, explosives, and dyeing industry.industry.

Therapeutic drugs & CancerTherapeutic drugs & Cancer

Alkylating agents: melphalan, myleran – Alkylating agents: melphalan, myleran – AMLAML

MOPP – AMLMOPP – AML

Immunosuppressants: azathioprine and Immunosuppressants: azathioprine and cyclosporin – Lymphomacyclosporin – Lymphoma

Phenacetin – Renal & Bladder cancerPhenacetin – Renal & Bladder cancer

Hormones (estrogen, OCP’s, tamoxifen) – Hormones (estrogen, OCP’s, tamoxifen) – Endometrial carcinoma Endometrial carcinoma

Tumor Spread, Invasion & Tumor Spread, Invasion & Metastasis Metastasis

Direct Invasion (local)Direct Invasion (local)– Cellular multiplication, mechanical pressure, release Cellular multiplication, mechanical pressure, release

of lytic enzymes, decreased cell to cell adhesion, of lytic enzymes, decreased cell to cell adhesion, increased motility of cells, disruption of tumor-host increased motility of cells, disruption of tumor-host microenvironmentmicroenvironment

Metastases to distant organs through lymphatic Metastases to distant organs through lymphatic and blood systemand blood system

Metastases by way of implantation (tissue Metastases by way of implantation (tissue spaces, body cavities, cerebrospinal spaces)spaces, body cavities, cerebrospinal spaces)

Tumor Invasion & MetastasisTumor Invasion & Metastasis

Anoikis: homelessness – cells detach from their Anoikis: homelessness – cells detach from their matrix and undergo apoptosis.matrix and undergo apoptosis.Lytic enzyems are: Matrix metallo-proteinases Lytic enzyems are: Matrix metallo-proteinases such as type IV collagenase, Cysteine such as type IV collagenase, Cysteine proteinases such as cathepsin b and D, and proteinases such as cathepsin b and D, and Serine proteases such as urokinase-type Serine proteases such as urokinase-type plasminogen activator.plasminogen activator.Incresed expression of Twist expression causes Incresed expression of Twist expression causes a loss of E-cadherin-mediated cell to cell a loss of E-cadherin-mediated cell to cell adhesion.adhesion.Three step theory of invasion: attachment, Three step theory of invasion: attachment, degradation, and locomotion of the matrix. degradation, and locomotion of the matrix.

Clinical Manifestations of CancerClinical Manifestations of Cancer(IL-1, TNF, IL-6, IFN)(IL-1, TNF, IL-6, IFN)

Pain is one of the main complaints. 25% of all Pain is one of the main complaints. 25% of all cancer patients die with unrelieved pain.cancer patients die with unrelieved pain.

Fatigue is a second complaint.Fatigue is a second complaint.

Cachexia is from IL-6, IL-8, TNF.Cachexia is from IL-6, IL-8, TNF.

Anemia is secondary to TNF, IL-1, decreased Anemia is secondary to TNF, IL-1, decreased EPO, impaired iron utilization, and chemo/radio.EPO, impaired iron utilization, and chemo/radio.

Nausea & Vomiting is usually 2ry to chemo.Nausea & Vomiting is usually 2ry to chemo.

Depression, anxiety, and delirium occurs in 50% Depression, anxiety, and delirium occurs in 50% of patients.of patients.

Paraneoplastic SyndromesParaneoplastic Syndromes

Seen in 10% of cancer Seen in 10% of cancer patients.patients.Endocrine Manifestations:Endocrine Manifestations:– Ectopic ACTH (Cushing’s): Ectopic ACTH (Cushing’s):

SCLC, Bronchial carcinoidSCLC, Bronchial carcinoid– SIADH: Lung cancerSIADH: Lung cancer– Hypercalcemia: Lung (Sq.), Hypercalcemia: Lung (Sq.),

Renal, Myeloma, ATCLL Renal, Myeloma, ATCLL Hematologic Manifestations:Hematologic Manifestations:– Polycythemia: Renal, Liver Polycythemia: Renal, Liver – DVT/PE: Pancreas, LungDVT/PE: Pancreas, Lung

Gastrointestinal Gastrointestinal Manifestations:Manifestations:– Protein-losing enteropathyProtein-losing enteropathy– Anorexia, CachexiaAnorexia, Cachexia

Renal Manifestations:Renal Manifestations:– Membranous nephropathy: Membranous nephropathy:

stomach, lung, colon stomach, lung, colon Cutaneous:Cutaneous:– Acanthosis nigricans: GI Acanthosis nigricans: GI

cancer (Leser-Trelat) cancer (Leser-Trelat) – Dermatomyositis: Breast & Dermatomyositis: Breast &

Bronchogenic ca.Bronchogenic ca.Neurologic:Neurologic:– Myasthenia: Bronchogenic ca.Myasthenia: Bronchogenic ca.

Rheumatologic:Rheumatologic:– Hyperthtophic Hyperthtophic

osteoarthropathy: osteoarthropathy: Bronchogenic ca. Bronchogenic ca.

Tumor markersTumor markers(Biologic markers)(Biologic markers)

They are substances produced by cancer cells that are They are substances produced by cancer cells that are found on tumor plasma membranes or in the blood, found on tumor plasma membranes or in the blood, spinal fluid, or urine.spinal fluid, or urine.AFP : Liver, Germ cell tumorsAFP : Liver, Germ cell tumorsB-HCG: Germ cell tumorsB-HCG: Germ cell tumorsCEA: Colon, Pancreas, Lung, breastCEA: Colon, Pancreas, Lung, breastPSA: Prostate PSA: Prostate CA19-9: Pancreas, Billiary treeCA19-9: Pancreas, Billiary treeCA 125: OvarianCA 125: OvarianCA 15-3 or CA 27.29: BreastCA 15-3 or CA 27.29: BreastB-2-microglobulin: Myeloma, LymphomaB-2-microglobulin: Myeloma, LymphomaCatecholamines: Pheochromocytoma Catecholamines: Pheochromocytoma

FDG-PET ScanningFDG-PET Scanning

FDG is a glucose analog that is taken up FDG is a glucose analog that is taken up and trapped by tumor cells in most of and trapped by tumor cells in most of patients with cancer. The positrons patients with cancer. The positrons emitted by the F18 atom travel a short emitted by the F18 atom travel a short distance before they encounter an distance before they encounter an electron and undergo extinction with electron and undergo extinction with emission of a pair of photons in opposite emission of a pair of photons in opposite directions.directions.

Significance of FDG-PET scanSignificance of FDG-PET scan

Adds assessment to uncharacterized Adds assessment to uncharacterized nodules and more accurately stages the nodules and more accurately stages the tumor than CT.tumor than CT.

Intensity of uptake before tx is correlated Intensity of uptake before tx is correlated with survival: high uptake = negative with survival: high uptake = negative prognosis.prognosis.

More about PETMore about PET

It is a complement to CT in instances It is a complement to CT in instances where CT has failed to detect distant where CT has failed to detect distant metastatic disease, and advising biopsies metastatic disease, and advising biopsies for LN’s > 1.0 cm on CT or positive on for LN’s > 1.0 cm on CT or positive on FDG-PET. Biopsy is still advised for FDG-PET. Biopsy is still advised for radio-graphically enlarged LN’s even if radio-graphically enlarged LN’s even if FDG-PET scanning is negative. FDG-PET scanning is negative.

Cancer treatmentCancer treatment

Surgery is the goal standard.Surgery is the goal standard.– Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate

Chemotherapy: Lymphoma, Leukemia, Testicular, Chemotherapy: Lymphoma, Leukemia, Testicular, Choriocarcinoma, Ovary, Breast Choriocarcinoma, Ovary, Breast Radiation therapy: Breast, Uterus, Cervix, Lymphoma, Radiation therapy: Breast, Uterus, Cervix, Lymphoma, LungLungHormonal therapy: Breast, Prostate, Endometrial, Hormonal therapy: Breast, Prostate, Endometrial, AdrenalAdrenalImmunotherapy: Melanoma, RCC, Leukemia Immunotherapy: Melanoma, RCC, Leukemia Target therapy: Colon, Breast, Lung, RCC, Leukemia, Target therapy: Colon, Breast, Lung, RCC, Leukemia, Lymphomas Lymphomas

Progress in OncologyProgress in Oncology

New diagnostic methodsNew diagnostic methods

Preventive MedicinePreventive Medicine

New Targeted and Personalized New Targeted and Personalized Therapy Therapy

Palliative & Supportive CarePalliative & Supportive Care

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