Cancer Biology: An Overview

Cancer Biology

• Cancer description dates as far back as 3000 BC in Egypt.
• Hippocrates was the first physician to use the terms "carcinos" or "carcinoma" around 460-370 BC
• The Greek term "carcinos" was translated to the Latin word "cancer" by Celsus around 28-50 BC.
• Galen used the Greek word "oncos" (meaning swelling) around 130-200 AD to describe tumours.
• An abnormal growth in mass and uncontrolled cell proliferation results in a tumour or neoplasm (new growth).
• Cancer is characterized by uncontrolled growth and spread of abnormal cells; lack of control can result in death.

Cancer Cell Properties

• Cancer cells reproduce without control
• Invade and colonize other tissues

Epidemiology of Cancer

• Epidemiology is the study of the distribution and determinants of health-related states/events in specified populations
• Research is applied to control health problems.
• Cancer epidemiology focuses on cancer distribution, determinants and frequency.
• Cancer epidemiology seeks causative factors to formulate preventive strategies

Cancer Statistics

• Cancer is currently the 2nd leading cause of death globally.
• It accounts for an estimated 9.6 million deaths in 2018, or one in six deaths.
• Cancer is projected to become the 1st leading cause of death in the World in 2060.

Common Cancers (USA 2020 Projections)

• For females
• Breast cancer accounts for 30.3%
• Lung cancer accounts for 12.3%
• For Males
• Prostate cancer accounts for 21.5%
• Lung cancer accounts for 13%

Common Cancers (Globally)

• For Males
• Lung cancer, stomach cancer, and liver cancer are most common.
• For Females
• Breast cancer, lung cancer, and colorectal cancer are most common.
• Incidence measures the occurence of new cases of a condition
• Mortality measures number of deaths

Common Cancers (Turkey 2018)

• Breast cancer has an incidence of 10.6% with mortality of 4.7%
• Lung cancer has an incidence of 16.5% with mortality of 29.8%

Estimated US Cancer Cases (2007)

• For Males
• Prostate cancer represents 29% of cases.
• Lung and bronchus cancer represents 15% of cases.
• For Females
• Breast cancer represents 26% of cases.
• Lung and bronchus cancer represents 15% of cases.

Lifetime Probability of Cancer in Men (2001-2003)

• All sites: 1 in 2
• Prostate: 1 in 6

Key Definitions

• Cancer: Any malignant tumour
• Tumour: Nonspecific term for lump or swelling; in current usage, it is a synonym for neoplasm
• Neoplasm: New growth, an aberrant proliferation of cells
• Neoplasia: A disease of cells characterized by alteration of normal growth regulatory mechanisms
• Metaplasia: Adaptive substitution of one adult tissue type for another under stress.
• Metastasis: Discontinuous spread of a neoplasm to distant sites via seeding through body cavities/vessels or direct transplantation

Biological and Clinical Behavior of Cancers

• Tumour grade classifies cancer cells based on microscopic appearance and the likelihood of growth/spread.
• Cancer stage refers to the extent or severity of the cancer, based on location, size, and lymph node involvement.

Histologic Grade

• Refers to how closely tumour cells resemble normal cells of the same tissue type.
• Tumours are graded as well, moderately, and poorly differentiated.
• Differentiated tumour cells resemble normal cells and grow/spread slower compared to undifferentiated cells.
• Undifferentiated tumours lack histological tissue-of-origin clues and are highly malignant.

Nuclear Grade

• Evaluation of the size and shape of the nucleus in tumour cells
• Evaluation of the percentage of tumour cells engaged in division/growth.
• Low nuclear grade cancers grow and spread more slowly compared to high nuclear grade cancers.

Tumor Grading Significance

• Pathologists describe tumour grade by four degrees of severity
• Grade 1/2 tumors resemble normal cells, tend to grow and multiply slowly, and are least aggressive.
• Grades 3/4 do not look like normal cells and tend to grow/spread faster than lower grade tumours.

Guidelines for Grading Tumours

• GX: Grade cannot be assessed (undetermined grade)
• G1: Well-differentiated (low grade)
• G2: Moderately differentiated (intermediate grade)
• G3: Poorly differentiated (high grade)
• G4: Undifferentiated (high grade)

Cancer Stage Components

• Size, extent of invasion, penetration of anatomic boundaries by the primary tumour
• Presence and number of lymph nodes involved with metastatic spread
• Presence of distant metastasis
• Stage 0: Carcinoma in situ, a malignant neoplasm not yet invaded through the basement membrane.
• Stage III: Malignancy has spread widely through the body.
• Stages I and II: Vary somewhat in specific definition depending on the tumour type/location under consideration.

Histogenesis

Neoplasms classification is based on tissue origin, which forms the basis for tumour nomenclature.

Benign Tumors

• In Benign tumors, the suffix "oma" is attached to the prefix designating the cell type from which the tumour arises.
• Adenoma: Benign epithelial neoplasm that produces a gland-like pattern / derived from glands.
• Papilloma: Benign tumour of the surface epithelium of neoplastic cells growing outward from the surface cover/finger-like stroma processes.
• Polyp: Pedunculated projection arising from mucosal/skin surface; may/may not be neoplastic.

Malignant Tumors

• They are classified the same as benign tumours but with additions.
• Carcinoma: Malignant neoplasm of epithelial cell origin (usually squamous)
• Sarcoma: Malignant neoplasm originating in mesenchymal tissues, such as fibrous tissue
• Further classification is based on the cell component, ie Squamous cell carcinoma, Adenocarcinoma, and Fibrosarcoma
• Undifferentiated tumour cells lack histologic classification criteria and are usually highly metastatic.

Tissue Types

Epithelium

• A thin layer of cells forming a tissue that covers body surfaces and lines hollow organs.

Connective Tissue

• Connects and anchors parts, providing support, strength, insulation, padding, and form.
• Fibroblasts, Adipocytes, Macrophages, and Mesenchymal cells are cell types that makes it up.

Blood and Lymph

• Hematopoiesis (blood cell development) occurs primarily in the bone marrow in adults
• The lymphoid cells originate from the bone marrow and thymus.
• Erythrocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes, and macrophages are all different types of blood cells.

Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Capable of invasion and metastasis
• Capable of inducing neoangiogenesis
• Genetic instability

Benign versus Malignant Tumors

• Benign tumors have a typical structure for tissue origin/expansion without a capsule.
• Malignant tumors tend to have an atypical structure, they are infiltrative and expansive, do not have a capsule.
• Metastasis is frequently present in malignant tumors but absent in benign ones.

Cell-Cell Interactions and Malignancy

• Alterations in cell-cell interactions and the formation of new blood vessels are associated with malignancy

Metastasis Cascade

• Cancer cells must break through the basal lamina, invade the capillary, travel through the stream, adhere to capillary wall, etc.

Biology of Invasion and Metastasis

• Infiltration and degradation of the basement membrane (BM)
• Binding through receptors for fibronectin and laminin
• Extracellular matrix (ECM) enzymatic digestion
• Movement is chemotactic and is is mediated through autocrine motility factor (AMF).

Metastasis Characteristics

• Metastasis occurs when cancer spreads to other organs from primary site
• Tumor Origin Examples
• Breast often metastasizes to lungs, bone or brain
• Lungs often metastasizes to brain, bone, adrenal glands or liver.
• Prostate often metastasizes to bone
• Bone often metastasizes to liver or lung
• Colon often metastasizes to liver

How Often Does Metastasis Occur?

• Approximately 30% of cancers spread to other organs on finite time line
• Approximately 30-40% of cancers appear clinically free of metastasis
• Approximately 30% of cancers do not appear to metastasis at all,

Metastasis Speed & Size

• Metastasis may occur before the cancer has grown to a detectable size.
• Large tumors have a higher chance for metastasis than small ones
• Metastasis may be very infrequent or nonexistent for some cancers.

Metastasis Location

• Metastatic tumors display organ specificity based on tissue of origin.
• Paget's theory: Cells are dispersed randomly but only grow in organs that provide the correct factors necessary for growth
• Ewing's theory: First site to which cancer metastasizes is the closest one in which there are small blood vessel

Types of Malignant Neoplasms

• Carcinomas arise from epithelial precursor cells
• Sarcomas arise from stromal or mesenchymal components of organs
• Undifferentiated Neoplasms is where its not possible to decide whether that have epithelial or mesenchymal orginin.
• Carcinosarcomas and malignant teratomas shows Mixtures of cells having mixed

Cancer Warning Signs

• Change in bowel or bladder habits
• A sore that does not heal
• Unusual bleeding or discharge
• Thickening or lump in breast or elsewhere
• Indigestion or difficulty swallowing
• Obvious change in a mole or wart
• Nagging cough or hoarseness
• Unexplained symptoms lasting longer than 2 weeks

Cause of Cancer

• Cancer is caused by an accumulation of genetic mutations, typically over 5 or more.
• Over 300 genes have been shown to be altered in human tumours and many still remain undetermined.
• Cancer is a term that encompasses many different genetic diseases that result in inappropriate cellular growth

Tumor Formation

• Tumour formation is a multistage process of genetic alteration.
• Gene Types that Are Mutated During Tumorigenesis
• Cell Growth
• Cell Death (Apoptosi )
• DNA Repairs
• Angiogenesis
• Cellular Cohesion
• Drug Xenobioti Metabolism
• Drug Resistance

Genetic Changes That Alter Cell Proliferation

• Mutations that result in unrestrained cell proliferation occur in two classes of genes:
• Oncogenes: products of proto-oncogenes stimulate cell proliferation.
• Tumor Suppressor Genes: Genes that encode proteins that inhibit cell proliferation and ensure stability of the genome.

Growth Factor Signal Transduction and Cancer

• The signalling cascade involves multiple cellular elements to transfer signals from the plasma membrane to the nucleus for expression.
• Growth factors in normal cells serve as environmental signals and regulate growth, proliferation, and survival but are deregulated in cancer.

Raf Kinase and Cancer Drugs as Targets

• Signal transduction intermediates can be targets for anti-cancer.

Skin Cancer Processes

• H-Ras Mutation is related to skin cancer
• It effects Ras activation
• The chemical protocols
• Is related to the PKC /MAPK pathway

Mammalian Cell Cycle Phases

• Phases Include G1, G2, Mitosis, DNA synthesis

Kinase & Cyclin

• Kinase catalytically active protein acts to phosphorylate a substrate.
• Cyclin acts as a regulatory subunit

p53 Role in Cancer

Description

• P53 is the most commonly mutated gene in all human tumors and a transcription factor
• Mutations are present in over 90% of human tumors.
• Functions by binding with DNA and is involved in growth arrest, apoptosis, DNA repair, and angiogenesis

Genetic Mutations Effect

• Mutations that affect the pRb-signaling pathway have been documented in nearly every type of adult tumor

DNA & Cancer

• Over 100 genes participate in DNA repair, even in organisms with very small genomes
• Genetic instability (elevation of mutation rate) permits sufficient mutations to generate human cancer.
• DNA repair mechanisms promote genetic stability and prevent cancer, so defects in repair genes often contribute

Xeroderma Pigmentosum

• Autosomal recessive disorder caused by mutations in any of 7 DNA repair genes
• Patients have severe light sensitivity, severe pigmentation irregularities, and early onset of skin cancer
• Originates most frequently in the abdomen, The overall survival rate is 50%

Genetic Lesions

• Generic Lesions that usually one gene
• Point Mutations
• Frame Shift Mutations
• Insertions/Deletions
• Amplification -Translocations
• Chromosomal Loss

Oncogene

• The prototypic TK oncogene is bcr/abl. The bcr/abl fusion oncogene is formed when the c-abTK gene on chromosome 9 Is translocated to chromosome 22 and fused with part of the bcr gene on that chromosome
• The result protein as increase kinase activity and drive proliferation causing transformation Also signal Transductions intermediates can are targets for anti cancer drug

Proto-oncogene Myc

• Has Genetic changes which affects
• Apports’s
• Genomic instability
• Growth, transformation, differentiation, angiogenesis

Skin Cancer

• Has Genetic changes which affects
• Actinic ketosis
• Basal cell Carinoma
• Squamous cell

Cell Cycle Arrest Function

Growth arrest and Mammalian cell growth

Cancer Angiogenesis

Tumour Mast cells Macrophages Angiogenic Growth. Extracellular matrix

MultiStage model

Mutations don’t happen all together and they take long to accumulate Also genetic alterations are typical “ Loss of Function” function and requirements that both genetics loci are altered Over 300 different genes have been shown to the altered in human genes and.Many still remain underterminate