Lecture 1

Leading cause of cancer death in USA: Lung cancer / Most common in USA: Prostate cancer for men and breast cancer for women

Most common cause of cancer in jordan

Males: Lung cancer followed by colorectal cancer

Females: Breast cancer followed by colorectal cancer

Environmental factors are the predominant cause of cancer

Stomach cancer is common in Japan

One third of deaths from cancer are caused by obesity, physical inactivity, smoking, alcohol and low veg diet. • Smoking is responsible for 20% of cancer deaths.

 Most common childhood tumors: leukemias, lymphomas, CNS tumors and soft tissue and bone sarcomas.

The difference between a neoplastic and non-neoplastic process is the presence of specific mutations in neoplasms.

Nevi (nevus) are benign tumors of melanocytes / Melanoma is a malignant tumor of melanocytes

(exceptions) Some benign neoplasms can be dangerous (like brain tumors) / Some malignant tumors are highly curable , e:g Hodgkin lymphoma

lipoma: benign tumour arising from fat tissue / Adenoma= benign epithelial neoplasm forming glands or neoplasm derived from glands

Polyp: mass projecting above mucosal surface (MACROscopic)

Teratoma: mixed tumor containing elements of more than one germ cell layer / Mature = benign immature = malignant

Hamartoma: Mass of disorganized tissue indigenous to a particular site

Choristoma: Heterotopic rests of cells, normal in appearance but present in an abnormal location (Congenital anomaly)

Malignant OMAs: Melanoma • Seminoma • Lymphoma • Mesothelioma • Multiple myeloma ( MMM SL)

Lecture 2

Tumour stage is the single most important prognostic factor.

Anaplasia is a hallmark of cancer / Tripolar mitosis = Mercedes sign

**Exceptions: Leiomyoma of uterus: can grow rapidly during pregnancy due to high estrogen level (shrink in menopause)

Local invasion is the second most important feature to differentiate benign from malignant neoplasms

Metastasis is the most important feature of malignancy

Basal cell carcinoma of skin doesn’t metastasize

•CNS tumors rarely metastasize

• Bone =osteogenic sarcoma usually found to be metastasized before discovering the primary tumor

Routes of metastatic spread

• 1. seeding within body cavities (Ovarian cancer through peritoneal cavity)

2. lymphatiC (Carcinomas)

• 3. hematogenouS (Sarcomas) (Liver and lungs are the most common sites of spread)

Lecture 3

Genes involved in cancer:

Proto Oncogenes/ Tumor suppressor genes/ DNA repair Genes/ genes that regulate Apoptosis/ genes that affect the interaction between tumour cells and host cells (esp relation with immune system)

oncogenes are dominant // Important oncogenes : RAS and ABL

Tumor suppressor genes are recessive genes // RB  gene and TP53 gene

Genes that regulate apoptosis or DNA repair may be dominant or recessive.

Occur mainly in haematogenous neoplasms

Translocations can cause cancer if they increase expression of a protooncogene. This can happen by two mechanisms:

• 1. Removing the proto-oncogene from its normal, regulated locus to a new position where it becomes under influence of a highly active promoter. (MYC moved close to IG locus)

• 2. Translocation forms a new fusion gene that encodes a novel protein. (ABL-BCR fusion creating a new tyrosine kinase resulting in leukemia) (Philadelphia chromosome) (t9:22)

Genes can be amplified by: 1-homogeneously stained region (HSR) = increased copies of the gene present within the chromosome :2.Double minutes: extra copies of the gene separated from the chromosome.

Deletions: More in non-hematopoietic solid tumors // Second most common karyotypic abnormality. // Result in loss of tumor suppressor genes • 2 copies of the tumor suppressor gene need to be lost, usually one by point mutation and another by deletion

Aneuploidy: • Result from errors of the mitotic checkpoint

microRNAs:  inhibit gene expression post-transcriptionally = repress translation or cleave mRNA

• Epigenetics are reversible, heritable changes in gene expression that occur without mutation // occurs through DNA methylation and histone modification

DNA methylation= more methyl groups lead to more silencing.

 • 1.Global DNA hypomethylation : increases expression of genes. Also causes chromosomal instability

 • 2.Selective promoter hypermethylation of tumor suppressor genes: silenced

Lecture 4:

For cancer to develop we need: a- 8 hallmarks // b- 2 enablers // c- correct microenvironment

The eight hallmarks • 1. self sufficiency in growth signals • 2. insensitivity to growth inhibitory signals • 3. evasion of cell death • 4. limitless replicative potential • 5. sustained angiogenesis • 6. ability to invade and metastasize • 7. reprogramming of metabolism • 8. evasion of the immune system

Enablers: 1-genomic instability 2-inflammation ///  Tumor microenvironment: This        is obtained from the host cells:Stromal cells,        mainly        fibroblasts and pericytes

1.Self sufficiency in growth signals

Growth factors:

• GF can be synthesized by tumor cells or host stromal cells

• glioblastomas produce PDGF and express its receptor

Growth receptors:

2 ways

1- overexpression of receptor

2- mutant receptor protein

Gene        encoding her2/neu is        amplified in 25-30% of breast cancers and adenocarcinoma of lung, ovary        and salivary gland

• High        level of HER2/Neu protein in breast        cancer        worsens prognosis (results in more proliferation)

Signal Proteins:

• Main        signal        transducing proteins involved: RAS and ABL

RAS

ABL

1- most common mutated gene in humans (in 30% of cancers)

2- higher incidence in colon and pancreatic cancers

ABL-BCR translocation Results in a hybrid gene

The hybrid gene produces novel tyrosine kinase which is always active and stimulating proliferation…This is the        Philadelphia chromosome

Uses 2 pathways: 1- RAF-MAPK // 2-PI3K AKT mTOR

RAF mutated in 60% of melanomas

ABL-BCR pathway activates all the downstream signals of ras

Activated (mutated) by 1- point mutation in GTP binding pocket

2- Mutation in GTPase activity

Found in CML (chronic myelogenous leukemia)

Imatinab/gleevec (kinase inhibitors) used to treat CML

Nuclear transcription factors:

Most common in humans: MYC // MYC activates cyclins and CDK and inhibits CDKI

Cyclins: D E A B

Cyclin D activated in many tumors mainly lymphomas

Second hallmark of cancer: insensitivity to growth inhibitors:

Main genes/pathways: 1. RB gene 2. TP53 gene 3. TGF beta pathway 4. Contact inhibition 5. APC gene

RB gene: directly or indirectly inactivated in most cancers // negative regulator of cell cycle (regulates G1/S checkpoint)

Works by binding E2F preventing it from transcribing Cyclin E. it does so by

  1. Preventing E2F from interacting with other proteins 2. Recruits proteins inhibiting E2F promoter

RB is active when HYPOphosphorylated and active when phosphorylated

Growth signals cause cyclin D expression. Cyclin D complexes with CDKs… these complexes phosphorylate and inactivate RB.

certain viruses can deactivate RB by hyper-phosphorylating it

RB is named after a tumor called: Retinoblastoma   // 60 % sporadic, 40% familial - In familial cases the predisposition to develop the tumor is inherited as an autosomal dominant trait

RB gene is found on chromosome 13 (13q14)locus // People with inherited RB have increased risk of other cancers.. Mainly osteosarcomas and soft tissue sarcomas

Loss of normal cell cycle control is found in all tumors through mutations of RB, cyclin D, CDK4 or CDKN2A (which is a CDKI)

TP53:

P53 monitors internal stress whereas RB senses external signals

P53 is triggered by several stresses: anoxia, inappropriate oncogene activity (MYC or RAS) or DNA damage.