Cancer Genetics, Cancer Cell Biology & Angiogenesis

CANCER&Genetics,Cell Biology,

ANN MEREDITH U. GARCIA, MD, FPCP, DPSMO, MCMMOInternal Medicine – Medical Oncology

Angiogenesis

Harrison’s Principles of Internal Medicine 19E

Characteristics & types of cancer

Tissue invasion

Avoidance of cell death Ability to metastasize

Unregulated cell division

CANCER TYPE TISSUE OF ORIGINCarcinomas Epithelial tissueSarcomas Mesenchymal tissuesLeukemiasLymphomasPlasma cell dyscrasias

Hematopoietic tissue

CANCER

Cancer is a genetic disease…

http://web2.uconn.edu/http://www.bu.edu/

…with a clonal origin

http://www.nature.com/

Critical discriminating feature between neoplasia and hyperplasia

The multistep nature of cancer

Multiple cumulative mutational events

http://img2.tfd.com/

Types of cancer genes

ONCOGENES+ (+) = +

– Positive influence on tumor formation– Tightly regulated in normal cells, but acquire activating mutations in cancer cells– Mutations typically occur in a single allele (dominant)

TUMOR-SUPPRESSOR GENES

- (-) = +

– Negative impact on tumor growth– Loss of function in cancer cells– Knudson’s two-hit hypothesis: Both alleles must be inactivated for a cell to completely lose function (recessive)

Gatekeeper genes – Directly regulate tumor growthCaretaker genes (i.e., DNA mismatch repair genes)

– Affect cell growth indirectly, but control the ability of the cell to maintain the integrity of its genome– “Mutator” phenotype

Exert their effects on tumor growth through their ability to control cell division (cell birth) or cell death (apoptosis)

Oncogenesvs. tumor-suppressor genes

http://cisncancer.org/

The bad guys, turn abnormal cell growth on (go/gas pedal)

The good guys, turn cell growth off(stop/brake pedal)

Oncogene activation

http://23pairsofchromosomes.com/

• KRAS• Melanoma• Colorectal CA• Acute myeloid

leukemia (AML)• BRAF

• Melanoma• Lung CA• Colorectal CA

• ERBB2 (HER2)• Breast CA• Ovarian CA• Gastric CA• Neuroblastoma

• N-MYC• Neuroblastoma• Lung CA

• t(9;22) or BCR-ABL (Philadelphia chromosome)• Chronic myeloid

leukemia (CML)• t(8;14)

• Burkitt’s lymphoma

Oncogene activation

http://www.cubocube.com/

Oncogene products have been found to function at critical stepsin growth factor pathways.

Oncogene activation

Tumor-suppressor gene inactivation

http://slideplayer.com/

Loss of heterozygosity (LOH) in tumor DNA is considered a hallmark for the presence of a tumor-suppressor gene at a particular tumor location.

• Two major types of somatic lesions• Point mutations• Large deletions

Tumor-suppressor gene inactivation

Ahmed H. Biomarkers in Cancer. 2010;2:17–33

Gene silencing is an epigenetic change that leads to the loss of gene expression and occurs in conjunction with promoter hypermethylation and histone deacetylation.A general decrease in the level of DNA methylation is a common change in cancer.

Viruses* in human cancer

VIRUS ASSOCIATED CANCERSEpstein-Barr virus (EBV) Burkitt’s lymphoma

Hepatitis B virus (HBV) Hepatocellular CA

Human papillomavirus (HPV)

Cervical CA, anal CA, oropharyngeal CA

Human T-cell lymphotropic virus (HTLV)

T cell leukemia

Human herpesvirus 8 (HHV-8)

Kaposi sarcoma

http://medchrome.com/

Activation of growth-promoting pathways or inhibition of tumor-suppressor products in the infected cells*Not sufficient for cancer development

The hallmarks of cancer

Hanahan D & Weinberg RA. Cell. 2011;144:646-674

Signal transduction pathways


An elaborate integrated circuit operates within normal cells and is reprogrammed to regulate hallmark capabilities within cancer cells.

The hallmarks of cancer


Hallmark #1


• Loss of function of negative growth regulators & increased action of positive growth regulators

• Aberrant cell cycle control & loss of normal checkpoint responses

Cell cycle checkpoints

Rb

p53

Chromosomal instability

van Jaarsveld RH & Kops GJPL. Trends in Cancer. 2016;2(10):561-571

A number of mitotic checkpoint genes are found mutated or abnormally expressed in various tumors.

Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes.

Hallmark #2


• Inactivation of p53 & increases in Bcl-2 family members

• Enhanced survival of cells with oncogenic mutations & genetic instability

• Clonal expansion & diversification within the tumor without activation of apoptotic pathways

Inhibition of apoptosis

Petronelli A, et al. Drugs Fut. 2005;30(7):707

The evolution of tumor cells to a more malignant phenotype requires the acquisition of genetic changes that inhibit apoptotic pathways and promote cancer cell survival and resistance to anticancer therapies.

EXTRINSIC PATHWAY INTRINSIC PATHWAY

Hallmark #3


• Loss of Rb, p16, & p53 pathways

• Telomerase expression

Telomere shortening & senescence

Resonance Research Foundation, Inc.

DNA polymerase is unable to replicate the tips of chromosomes

Loss of telomeric repeats & gradual telomere shortening

p53-regulated DNA-damage checkpoint response

Senescence or growth arrest

Reactivation of telomerase expression

in cancer cells

Nonfunctional pRB & p53

Hallmark #4


• Nonresponsiveness to external growth-inhibiting signals

Gompertzian tumor kinetics

http://highered.mheducation.com/

The growth fraction of a tumor declines exponentially with time.Not every daughter cell produced by a cell division is itself capable of dividing.

Hallmark #5


• Increased gene expression of proangiogenic factors by tumor or stromal cells

• Loss of negative regulators

Angiogenic switch

Markkanen JE, et al. Cardiovasc Res. 2005;65(3):656-664

A phase in tumor development when the dynamic balance of pro- and antiangiogenic factors is tipped in favor of vessel formation by the effects of the tumor on its immediate environment

SPROUTING

Angiogenic switch

Koch AE & Distler O. Arthritis Res Ther. 2007;9(Suppl 2):S3

Abnormal tumor vasculature

Cao Y. Front Biosci. 2009;14:3962-3973

Hallmark #5


• Epithelial-mesenchymal transition (EMT): Loss of cell-cell contacts & increased production of matrix metalloproteinases

Epithelial-mesenchymal transition (EMT)

Angadi PV & Kale AD. Indian J Health Sci Biomed Res. 2015;8:77-84

Malignant cells that metastasize undergo EMT as an important step in that process but retain the capacity for unregulated proliferation.

Metastasis

Emerging hallmarks &enabling characteristics


Enabling characteristic #1


• Defects in DNA repair pathways

• Accumulation of a variety of mutations & heterogeneity

Enabling characteristic #2


• Production of tumor-promoting bioactive molecules to the tumor microenvironment

• Release of chemicals, notably reactive oxygen species, that are actively mutagenic


Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression.The immune inflammatory cells present in tumors can include both tumor-promoting as well as tumor-killing subclasses.

The dynamic tumor microenvironment





Emerging hallmark #1


• Downregulation of MHC class I & II molecules

• Induction of T cell tolerance• Inhibition of normal

dendritic cell &/or T cell function

• Antigenic loss variants & clonal heterogeneity

• Increase in regulatory T cells

Tumor-host interactions that suppress the immune response to the tumor

Immune checkpointsT-cell activation is kept under check through inhibitory signals from the interaction of CTLA-4 and its ligands, CD86 or CD80.The interaction between the PD-L1 and PD-1 receptors also leads to inhibition of T-cell activation and effector function.

Emerging hallmark #2


• Shift to aerobic glycolysis

Warburg effectProliferative tumor tissues, especially in the setting of hypoxia, use aerobic glycolysis to generate energy for cell survival and generation of building blocks for new cells.

CLINICALImplications

Familial cancer syndromes

Ambry Genetics

The affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene.

Familial cancer syndromes

Ambry Genetics

Autosomal dominant – majorityAutosomal recessive – DNA repair abnormalities (xeroderma pigmentosum, Fanconi’s anemia)

Familial cancer syndromesSYNDROME GENE ASSOCIATED TUMORS

Familial adenomatous polyposis (FAP)

APC Intestinal adenoma, colorectal

Hereditary breast/ovarian cancer (HBOC)

BRCA1BRCA2

Breast, ovarian, colon, prostate

Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome

MSH2MLH1MSH6PMS2

Colon, endometrial, ovarian, stomach, small bowel, ureter

Li-Fraumeni syndrome TP53 Sarcoma, breastMultiple endocrine neoplasia (MEN)

Type 1Type 2a

MEN1RET

Parathyroid, endocrine, pancreas, pituitaryMedullary thyroid carcinoma, pheochromocytoma

von Hippel-Lindau syndrome

VHL Kidney, cerebellum, pheochromocytoma

Risk factors for hereditary cancer

Family history of cancerHaving 3 or more relatives on the same side of

the family with the same or related forms of cancer

Cancer at an early ageHaving 2 or more relatives diagnosed with

cancer at an early age, which may be different depending on the type of cancer

Multiple cancersHaving 2 or more types of cancer occurring in

the same relative

American Society of Clinical Oncology

Genetic testing

Personalized cancer treatmentbased on molecular profiles(precision medicine/targeted therapy)Dependent on the identification of sufficient actionable changes (mutations or pathways that can be targeted with a specific drug)

MUTATION TARGETED DRUG INDICATIONS

ALK Crizotinib Non-small cell lung CA (NSCLC)BCR-ABL Imatinib Chronic myeloid leukemia (CML)

Acute lymphoblastic leukemia (ALL)Gastrointestinal stromal tumors (GISTs)

BRAF Vemurafenib Malignant melanomaEGFR Erlotinib Non-small cell lung CA (NSCLC)

Pancreatic CA

Therapeutic targeting of the hallmarks of cancer


Thank you!

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Cancer Genetics, Cancer Cell Biology & Angiogenesis