Learning Outcomes

Cellular Proliferation and Cancer

▪Define the terms tumor, neoplasia, cancer, benign, malignant, and carcinoma in situ.

▪ Identify and differentiate types of cancers based on cell type, such as adenocarcinoma, lymphoma, or sarcoma.

▪ Define the following concepts: autonomy, transformation, anchorage-independence, immortal, anaplasia, pleomorphic, stem cells, tumor markers, clonal proliferation.

▪ Describe how the following mechanisms promote tumor growth: autocrine stimulation, increase in growth factor receptors, mutated cell-surface receptor, mutation in ras intracellular protein, and inactivation of Rb tumor suppressor.

▪ Define and relate angiogenesis to cancer growth.

▪ Describe the role of telomeres and telomerase in tumor development and compare and contrast the gene products of proto-oncogenes, oncogenes, and tumor suppressor genes.

▪ Describe how the following genetic events can activate oncogenes: point mutations, chromosome translocations, gene amplification, tumor suppressor gene mutation and loss of heterozygosity.

▪ Define mutagen and carcinogen.

▪ Describe the role of chronic inflammation and cancer cell development and list bacteria and viruses that can cause of cancer.

▪ Describe cancer cell growth and behaviour including steps for metastatic spread and mechanisms that favour or inhibit local spread of cancerous cells.

▪ Describe the mechanisms of the following environmental factors in cancer development: tobacco use, ionizing radiation, ultraviolet radiation, alcohol consumption, sexual and reproductive behaviour, physical activity, occupational hazards and exposure, air pollution, electromagnetic fields, and diet.

▪ Describe the common clinical manifestations of cancer: anemia, leukopenia, thrombocytopenia, infection, paraneoplastic syndrome, fatigue, and pain and the syndrome of cachexia.

▪ Describe methods for diagnosis of cancer including biopsy types.

▪ Compare and contrast the modalities for the treatment of cancer: chemotherapy, surgery, radiation, and immunotherapy

▪ Describe common side effects associated with cancer treatment in the following systems: GI tract, bone marrow, integument, and reproductive tract

Definitions: Cellular Proliferation and Cancer

Review

▪The following refers to areas of previous knowledge that applies to the current unit and will help to understand and apply the concepts during the lecture.

▪ It is recommended that previous lectures and resources are used to clarify details in areas as determined by the needs of you, the student.

Anatomy and Physiology:

There are 4 types of body tissues:

1. Epithelium

2. Connective tissue

3. Muscle

4. Neural

▪ Epithelium is classified into epithelia and glands.

– Epithelia can be further divided by cell structure, each one having distinct properties related to the locations in which they are found.

– Epithelia can be classified by cell shape (squamous, columnar) and density (simple, stratified).

o The general exception is pseudostratified epithelium lining the respiratory tract.

– There are 2 types of glandular tissue:

1. Exocrine

2. Endocrine

▪ There are 3 types of connective tissue (CT):

1. CT Proper

2. Fluid CT

3. Supportive CT

Clinical Chemistry Review Topics:

▪ DNA structure, transcription, and gene expression

▪ Terms: gene, chromosome, chromatin, histone

Pathophysiology Review Topics:

▪ Pathological cellular adaptation

Cancer

▪ Cancer: Derived from the word for crab (it can spread), karkinoma

▪ Cancer is a leading cause of death in Canada and is responsible for 30% of all deaths. Cancer and then heart disease. 1 in 3 people in Canada gets cancer.

▪ Most common cancer types in Canada:

– Breast → Prostate → Colorectal → Lung

Tumor

▪ Also called a neoplasm = new growth

▪ Classified as either benign or malignant (see below comparison)

Comparing Benign and Malignant Tumors (Table)

Cancer Cells in the Laboratory

Characteristics of Cancer Growth

▪ Less need for growth factors

▪ Lack of contact inhibition

▪ Anchorage independence

– Do not require attachment to a surface and therefore will continue to grow when suspended in soft agar gel

▪ Immortality – do not die

Human cancer cell lines:

▪ Can grow independently

– A piece can be dissected from a tumor, cells teased and frozen/preserved in tubes and use to study later.

– These cells can live forever and are used for research (drugs, animals, immunity).

▪ Can create tumors and metastasize in mice with no immune system

▪ Examples of human cancer cell lines (used for research)

– HELA cells (cervical cancer)

– MDA (breast cancer)

– DU145 (prostate cancer)

Tumor Classification and Nomenclature

Benign Tumors

▪ Naming according to the tissue of origin

▪ Mostly include the suffix “-oma”

▪ Common examples:

– Glioma = brain

– Chondroma = cartilage

– Leiomyoma = uterine fibroid

– Lipoma = fat tissue

– Benign melanoma = skin

▪ However, use a cautionary approach to benign tumors

– Not all tumors ending in “oma” are benign, SOME CAN BE MALIGNANT (e.g. melanoma and lymphoma).

– *A benign tumor can progress to become malignant and requires frequent monitoring and/or treatment depending on stage, type, risk, and patient preference.

– *Benign does not mean asymptomatic. An otherwise benign tumor may cause other symptoms depending on the location and relationship to other organs.

o For example, compression of blood vessels and organs (especially those that do not adapt to invasive growth such as the brain)

Malignant Tumors

▪ Key characteristics of malignant tumors:

– Anaplasia = poorly differentiated

– Pleomorphic = vary in size/shape

– Metastasize – the most deadly characteristic of malignant

cell carcinoma

o Anaplastic carcinoma (heterogeneous/undifferentiated)

– Connective tissue (sarcoma) = CT, muscle or bone

o 90% diagnosed in children and young adults

o Fibrosarcoma = fibrous tissue

o Osteosarcoma = bone

o Rhabdomyosarcoma = muscle

o Leukemia (blood origin, still CT)

o Lymphoma = lymph node

Other Nomenclature

▪ Carcinoma in situ (CIS)

– High grade dysplasia

– Local (pre-invasive) epithelial or glandular origin

– “local” – hasn’t invaded the basement membrane. Usually intraductal, confined to the duct, cannot leave

▪ Cancer of unknown primary origin (CUP)

– Metastasized but do not know where from

– If you find cells and tissues outside of where they are supposed to be = CUP

– Example: squamous epithelial cell in the lung

Tumor Microenvironment

▪ Cancer cells are surrounded by a complex microenvironment:

– Comprised of numerous different cells:

o Endothelial cells of blood and lymphatics

o Stromal fibroblasts

o Immune/ inflammatory cells

– Often hypoxic → angiogenesis

▪ This is known as tumour microenvironment and determines the tumour behaviour and response -or lack of- to therapy

▪ The tumour cell makeup (microenvironment) contributes to tumor heterogeneity:

– Every tumor matures in its own way, the composition of cells is different, making a unique microenvironment.

o It is like an ID

– This is the reason why some tumors but not others of the same type resist chemotherapy (subject of research)

Cancer Metabolism

▪ Cancer cells have distinct nutritional requirements compared to normal cells and therefore must develop mechanisms to meet these requirements. This includes:

– Extract nutrients from blood stream

– Use aerobic glycolysis (glycolysis (no kreb’s cycle) even in presence of O2) to support growth and proliferation

o Glycolysis makes 2 pyruvates (2 ATP) and is anaerobic process (typically)

o Because cancer cells use glycolysis even in aerobic conditions (i.e. with oxygen present) they never use oxygen and will always have energy to divide.

o This is unlike obligate aerobes (like human cells) that will stop dividing and eventually die in the absence of oxygen.

– Divide even in hypoxic or acidic states

o The tumor environment becomes acidic from glycolytic energy production as a result of the production of ketones from acetyl CoA and lactate.

Cancer and Angiogenesis

▪ Angiogenesis: Growth of new vessels

▪ Advanced cancer can secrete angiogenic factors

– Vascular endothelial growth factor (VEGF)

– Platelet derived GF

– Basic fibroblast GF

▪ Why do tumors need new BV given they don’t need oxygen??

– THEY NEED THE NUTRIENTS

Genes, DNA and Cancer

Telomeres and immortality

▪ Normal somatic cells cannot divide indefinitely

▪ Telomeres:

– Protective caps in chromosomes’ ends

o E.g. TTAGGG is a sequence that caps the end of a chromosome in somatic cells

– Become shorter with each cell division

o As the cells divide telomeres become closer together until eventually, they are lost

▪ Telomerase adds new DNA repeats to telomeres allowing cells to divide indefinitely.

– Stem cells express telomerase

– Cancer cells activate telomerase

o This allows unlimited division and proliferation

▪ CANCER CELLS ARE IMMORTAL BECAUSE OF THEIR TELOMERES

Oncogenes and Tumor-Suppressor Genes

▪ Oncogene:

– Abnormal gene that promotes tumors.

▪ Proto-oncogene:

– Normal gene that directs protein synthesis and cellular growth.

– Can turn into an oncogene due to:

o Mutation

• Point mutation in RAS gene (pancreatic and colorectal cancer)

• Point mutation of EGF receptor tyrosine kinase (lung cancer)

o Chromosomal translocation

o Activation/increased expression

• Gene amplification is one example that can result in increased expression of gene.

o E.g. N-MYC oncogene is amplified in 25% of childhood neuroblastomas.

o The HER2 gene is amplified in 20% of breast cancers.

▪ Tumor-suppressor genes (antioncogenes)

– Gene that encodes proteins which in their normal state negatively regulate cell proliferation or promote apoptosis.

Prevent cancer

o These genes must be inactivated for cancer to occur

o Both tumor suppressor genes from mom and dad must be inactivated for an oncogene to be activated

Genetic changes in Cancer – Examples

Point mutations in proto-oncogenes

– RAS gene mutations: pancreas and colorectal cancers

– EGF receptor tyrosine kinase: lung cancer

Chromosomal translocation

– T(8;14) results in activation of MYC proto-oncogenes → Burkitt lymphoma

o MYC gene is usually on chromosome 8 and is regulated at low levels of producing lymphocytes.

o The chromosomes translocate, the MYC gene is now on chromosome 14 under B cell IgG control.

o MYC genes are now produced at high levels, hence the lymphoma (high

lymphocytes).

– T(9;22) results in BCR-ABL fusion genes → chronic myeloid leukemia (CML)

o “Philadelphia chromosome” (name referring to high levels of CML in Philadelphia in the 60s)

o BCR is on chromosome 9, and ABL is on chromosome 22. The 2 genes are

then fused together as a fusion gene ; new chromosome 22.

o BCR-ABL fusion gene codes for unregulated protein tyrosine kinase that promotes growth of myeloid cells. CML = chronic myeloid (myelogenous) leukemia

Gene amplification

– Duplication of a gene that results in multiple copies

– N-MYC oncogene is amplified by 25% in childhood neuroblastoma cases

– HER2 gene is amplified in 20% of breast cancers

Loss of function of tumor suppressor genes

– Retinoblastoma (RB1 gene)

– Neurofibromatosis (NF1 gene)

– Breast cancer (BRCA1 gene)

o Use it to test family members as well → could be predisposed to cancer

Tumor markers

▪ Substances produced by cancer cells

▪ Present on cell membranes, in blood, CSF or in urine

▪ Used to:

– Screen and ID individuals at high risk for cancer

– Diagnose specific types of tumors

– Observe clinical course of cancer and

treatment effectivenss

▪ The problem = specificity, there are a lot of false positives

– Often the presence of a marker cannot tell where the tumor is or what type

– Example: CA125 is present in many cancer (lung, gut, pancreas, breast, ovaries, endothelium)

Cancer stem cells

▪ Stem cells have the ability of self-renewal

and differentiation

– Stem cell division can create new stem cells

– Stem cells are pluripotent:

o Have the ability to differentiate into multiple types of cells

▪ Some cancer cells possess characteristics of stem cells

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