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