Exam 3 - Module 11 Cancer Biology: Terminology and Characteristics

Cancer Biology Overview

• Cancer is a major cause of death in the developed world and is understood to be over 100 different diseases
• It results from genetic and epigenetic changes accumulating over time, influenced by environment, heredity, and behavior
• Advances in treatment strategies, supportive care, and individualized therapies are increasing effective treatment options

Cancer Terminology and Characteristics

• Cancer comes from the Greek word "karkinoma" for crab, used by Hippocrates to describe tumor projections
• Tumors originally referred to any swelling from inflammation, now reserved for new growth (neoplasm) from abnormal, uncontrolled proliferation
• Cancer specifically refers to malignant tumors, where abnormal cells divide without control and can invade other tissues, according to the National Cancer Institute (NCI)

Benign Tumors

• Benign tumors are encapsulated, contain well-differentiated cells and organized stroma, and retain normal tissue structure
• They do not invade beyond their capsule or spread to other locations, and mitotic cells are rare
• These tumors are named with the suffix "-oma" plus the tissue of origin (e.g., leiomyoma of smooth muscle)
• Benign tumors of the colon or stomach are polyps, and those of melanocytes are nevi
• They can cause morbidity or be life-threatening by compressing normal tissue, causing ischemia or hormone overproduction

Malignant Tumors

• Malignant tumors are distinguished by rapid growth, loss of differentiation (anaplasia), and absence of normal tissue organization
• Malignant cells are pleomorphic, with variable size and shape, large dark nuclei, and frequent mitotic cells
• These tumors may have disorganized stroma, lack a capsule, and invade nearby tissues
• Metastasis, the ability to spread far from the origin, is the most important characteristic

Cancer Nomenclature

• Cancers are named by the cell type of origin: carcinomas from epithelial tissue (like mammary adenocarcinoma), sarcomas from mesenchymal tissue (connective tissue, muscle, bone, such as rhabdomyosarcomas of skeletal muscle)
• Lymphomas arise from lymphatic tissue, and leukemias from blood-forming cells
• Some cancers have historical names that do not follow the convention such as Hodgkin disease and Ewing sarcoma

Carcinoma in Situ (CIS)

• Carcinoma in situ refers to preinvasive epithelial tumors with atypical cells and increased proliferation, but remains localized in the epithelium
• These can occur in various sites, staying stable, progressing to invasive cancer, or regressing
• High-grade dysplasia in CIS is more likely to become invasive

Tumor Identification

• Proper identification of cancer is important for understanding causes, progression, spread, and treatment response
• Classification includes origin tissue and organ, distribution extent, microscopic appearance, and genetic changes

Hallmarks of Cancer

• Drs. Douglas Hanahan and Robert Weinberg defined hallmarks of cancer including eight hallmarks and two enabling characteristics:
  • Sustaining proliferative signaling
  • Evading growth suppression
  • Resisting cell death
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Activating invasion and metastasis
  • Deregulating cellular energetics
  • Avoiding immune destruction
• Genomic instability (mutator phenotype) and tumor-promoting inflammation

Biology of Cancer

• Cancer is a complex genetic disease where a tumor microenvironment is composed of cancerous and benign cells
• It is a disease of cumulative genetic changes over time through mutations in the DNA sequence, chromosome translocations, and gene amplification
• Epigenetic effects, like DNA methylation, can alter gene expression.
• Driver mutations drive cancer progression, while passenger mutations do not contribute
• Accumulation continues throughout progression to metastatic lesions and malignant transformation is driven by genetic changes

Tumor Microenvironment

• The tumor microenvironment plays a key role in cancer development
• Proliferation of cancer cells triggers proinflammatory mediator synthesis, recruiting immune cells, fibroblasts, adipocytes, mesenchymal stem cells, endothelial cells, and pericytes
• These cells form the stroma, affecting both populations through paracrine signaling, increasing proliferation and heterogeneity, and evolving stromal cells

Genomic Hallmarks

• Sustaining Proliferative Signaling: Cancer cells have mutations that stimulate cell growth
• Mutated or overexpressed proto-oncogenes lead to oncogenes and cause uncontrolled proliferation
• Activation can be through point mutations, gene amplification, or chromosomal translocations such as c-myc in Burkitt lymphoma and BCR-ABL in chronic myeloid leukemia)
• Signal transduction pathways involving growth factor receptors, RAS, PI3K, and MYC are often constitutively activated
• Cancers can secrete their own growth factors (autocrine stimulation), or stromal cells may produce excessive amounts

Evading Growth Suppression

• Normal cells receive anti-growth signals monitored by tumor suppressor genes like RB, with mutations causing persistent growth
• Inactivation of RB allows uncontrolled cell cycle progression as does the loss of p53 function which is common in cancer
• Loss of function mutations in tumor-suppressor genes inherited from familial retinoblastoma and TP53 in Li-Fraumeni syndrome, increase cancer risk

Genomic Instability

• Genomic instability results from defects in DNA repair mechanisms and caretaker genes, such as ataxia-telangiectasia and Fanconi anemia, are associated with increased cancer risk
• Genomic instability can arise from epigenetic silencing through DNA methylation which then silences tumor suppressing genes

Enabling Replicative Immortality

• Normal somatic cells have limited division potential due to the shortening of telomeres with each division that leads to cancer cells becoming immortal through activating telomerase or an enzyme that rebuilds telomeres
• Cancers also contain cancer stem cells that give them the ability to self-renew

Inducing Angiogenesis

• Tumors need a blood supply to grow and new blood vessels are essential to tumor growth and spread
• Cancer cells increase angiogenic factor secretion, while hypoxic conditions induce HIF-1a, a major regulator of angiogenesis, and its expression
• The tumor microenvironment and stromal cells secrete VEGF
• Cancer and stromal cells can increase Matrix Metalloproteinases which activates stored angiogenic factors

Reprograming Energy Metabolism

• Cancer cells exhibit aerobic glycolysis (Warburg effect) over mitochondrial oxidative phosphorylation (OXPHOS), even with sufficient oxygen
• The Warburg effect generates less ATP but provides metabolic intermediates for rapid cell growth which involves oncogenes and the mutant tumor suppressors
• The high glucose utilization of cancers is used for diagnosis 18F-Fluorodeoxyglucose (FDG) PET scans

Resisting Apoptotic Cell Death

• Apoptosis, or programmed cell death, eliminates aberrant cells through intrinsic (mitochondrial) and extrinsic (death receptor) pathways
• The balance between proapoptotic (e.g., BAX, BAK) and anti-apoptotic (e.g., BCL2) proteins regulates apoptosis
• Cancer cells resist apoptosis through loss of p53 function and reduce levels of death receptors, and inactivate death domain signaling complexes

Promoting Tumor Inflammation

• Chronic inflammation has been recognized as an important factor in cancer development
• Inflammation results from infections, irritant exposure, and autoimmune conditions and enhance the environment to recruit immune and inflammatory cells
• Tumor-associated macrophages (TAMs) promote tumor survival, and cancer-associated fibroblasts (CAFs) contribute to cancer progression and metastasis

Avoiding Immune Destruction

• Cancers express tumor-associated antigens detectable by the immune system, but can evade destruction through mechanisms
• Cancer cells evade the immune system by losing antigen expression, producing immunosuppressive cytokines, inducing immunosuppressive T-regulatory (Treg) cells, or expressing ligands for inhibitory receptors on T cells

Activating Invasion and Metastasis

• Metastasis spreads cancer cells which involves multiple steps to distant tissues and organs, which leading to cancer death
• Epithelial-mesenchymal transition EMT is the model for which involves a loss of polarity and increased apoptosis, which is driven by cytokines and interleukin 8 and the tumor microenvironment
• To achieve distant metastasis, cancer cells must invade local blood, survive in circulation and extravasate with the pattern determined by the vascular and lymphatic drainage

Clinical Manifestations of Cancer

• Clinical manifestations are diverse depending on the type and location, which include pain, and inflammation
• Paraneoplastic syndromes are symptom complexes triggered by a cancer but not caused by the direct local effects
• Manifestations also involve cachexia, anemia, fatigue, gastrointestinal tract issues, hair loss, skin changes, infections and lymphedema

Diagnosing and Staging Cancer

• Diagnosis requires a pathologist's examination of tumor tissue through biopsy procedures or cytology
• Cancer staging determines if the cancer has spread, involves determining the size, the degree of local invasion and the extent of spread to regional lymph nodes.
• Stage 1 is confined where stage 2 is locally invasive, stage 3 has spread to regional structures; and stage 4 has spread to distant sites and has a standard scheme

Tumor Markers

• Tumor markers are biochemical substances produced by benign or malignant cells, including hormones, enzymes, genes, antigens, and antibodies
• Tumor markers are used to screen for cancer but are not satisfactory for general population
• Examples include PSA for prostate cancer and CA-125 for ovarian cancer

Analysis

• Immunohistochemical and genetic analysis are important for cancer classification and treatment decisions through gross and light microscopy, protein expression analysis, and genetic analysis of tumors
• Gene expression using PCR, microarrays, or DNA sequencing can classify tumors, predict therapy response and contribute to medicine

Treatment of Cancer

• Evolved significantly to include surgery, radiation therapy, and chemotherapy and newer approaches with immunotherapy and targeted therapies

Classic Approaches

• Surgery plays many roles that range from diagnoses to treatment through radiation and chemotherapy

Radiation Therapy

• Radiation therapy leverages ionizing radiation to damage DNA and kill cancer cells while minimizing harm to normal tissue, which is effective for localized disease
• Chemotherapy will directly affect pathways in rapidly dividing cells can be used for adjuvant (after surgery), and neoadjuvant (before localized treatment)
• Immunotherapy is used to boost an immune response that Includes cancer vaccines and tumor targeting lymphocytes

Engineered T Cells

• These involve a CAR T-cell therapy and have shown significant success in hematologic cancers by helping to recognize cancer cells

Monoclonal Antibodies

• Damage cancer cells directly and facilitate cellular cytotoxicity in order to help repress T-cell immune responses and allowing tumors to be stopped from growing.

Cancer Disruption

• Targeted disruption of cancer uses drugs that target abnormalities of cancer cells
• Prevention is urgent and lifestyle changes are a focus and to the reducing exposures to certain areas with pollution.

Tumor Classification Summary

• Benign tumors are encapsulated with normal tissue structures
• Malignant tumors have a rapid growth rate and have the ability to metastasize
• Carcinoma in situ are pre-invasive epithelial tumors in cells and an increase production of cells

Cancer Development

• Genetic mutations and driver mutations leads to cancer, and creates a selective advantage over neighboring cells
• Tumor developments are a result of cancer being a genetic disease and has hallmarks that include uncontrolled cellular proliferation

Cellular Proliferation and Tumor Growth

• The normal state in the suppression of genes can lead to tumors and the genes stop the division if the are damaged and prevent mutation, which is why two mutations are required to stop tumors
• In terms of genetic instability the genomic integrity happens when there is an abnormality within a cell that leads to cancer and has an increase in mutations

Cancer Cell Mutations

• Cells have the ability to maintain themselves which is called immortality that then leads to the access of new blood known as angiogenesis causing the cancer to grow more
• Metabolically, cancer cells can favor aerobic glycolysis and have a resistance to cell death which involved programmed cell death

Cancer Cells and the Immune System

• Tumor promoting factors come from an inflammation within the immune system which then tries to destroy the tumors
• The spread of cells to other organs is a major cause and has different mechanisms in order to facilitate different aspects that have a potential to redifferentiate

General Notes on Tumors

• Syndromes are commonly caused by biologic substance being released the tumor as are cancer treatments such as surgery which can help in cases of metastasized cancer
• Radiation therapy can help in destroying cells as well with localized treatments and there are drug agents that help but they target both normal and cancerous cells
• Immunotherapy can lead to responses within the immune functions that fight cancer, while therapy increases the unique characteristics that are expressed from it

Genes, Environment, and Lifestyle

• The genetics have to due with environment that can cause cancer as well as the genes the person has which allows the epigenetics of the person to play a role
• Epigenetic help maintain the genome integrity and silencing the process of gene regulation
• The tissue can be helped by the environment that they are exposed to whether it be hormones or glucose

Factors for Cancer

• Cancer comes from inflammatory responses that come from the environment as well as lifestyle
• The complex relationships between environment, genetics, and the phenotype have connections to the complex risk cancer has

General Trends and Conditions

• There are many factors that influence cancer depending on the exposure to pollutants which will have long term affects on the person in question. Which can lead to other factors and genes to be expressed
• Early life exposure is key in stopping cancer from starting because the body can regulate the chemicals and toxins that can affect the genes through what an epigenetic mutation
• There are many high risk behaviors and carcinogens which can influence the outcome of a person

Contributing Risk Factors

• Taboo, nutrition, exposure, consumption and any other habits can have a large impact which leads to mutations and cancers
• Physical activity is a must to the body and the less one partakes increases the risks
• Infections can be a large indication of HPV and have the body get the exposure because it is a significant role as well as the use of synthetic chemicals

Review and Factors Involving Etiology

• Many chemicals, the environments, the people in the body all lead to different factors that go into the body
• Genetic mutations, early life, and the risk that has to do with the tumor all play a role

General Factors and Their Mechanisms

• Cancer, diet ,and exercise all play a role if not the main role in deterring the cancer progression because epigenetic can act in coordination
• Weight can play a role in the function and is one the major things that lead to a cancer diagnoses by decreasing levels

Radiation and Exposure

• Air Pollution will short life because it causes oxidative stress while radiation can cause more damage, it can also have a lower threshold
• There is a direct correlation with UV when it comes to cancer and must take care based on what the body is able to produce since certain ethnicities can be impacted through electromagnetic waves

Risk and Cancer Correlation

• Some direct correlations when it comes to people contracting certain cancers because of what there body is able to handle and have those reactions
• Infections are a very big role such as HIV that also have direct affect on the body

Multifaceted Overview

• The factors that are important and that people must be aware of and understand that decreasing the exposure will cause an environmental factor that prevents the illness from ever appearing

General Info on Etiology

• Proto-oncogenes are a gene made to protect you from having cancer and mutated genes can harm and contribute more
• There are many chromosomal aberrations and each one leads to an elevated result as well as risks due to family history
• The lack of a gene can cause damage to DNA and also in correlation is the impact to radiation

Pediatric Cancer Overview

• Cancer is rare in children and adolescences but it is still the leading death from diseases on all
• There improvement is largely due to targeted medical advancements that have played a significant role
• Pediatric cancer comes from mostly mesodermal with some being embryonal
• The diagnosis stems from leukemia and there the tumors and the risk is due to which group in demographics
• Childhood tumors share a connection in a peak time of development in which the cause is unknown and the link

Links and Notes on Pediatric Cancer

• Mostly all the cancers are linked to a chromosome and will then have genes that are linked to the risk
• Exposure to things like high dose amount of radiation that comes from drugs and it has been linked through breast to test for