11.1 From Notes - Understanding Cancer Biology

Cancer Characteristics

• Cancer includes over 100 diseases caused by age-related genetic and epigenetic changes
• Environment, heredity, and behavior affect cancer risk and treatment response
• Advances in treatment, supportive care, and individualized therapies have improved outcomes

Terminology

• Cancer comes from the Greek word "karkinoma," meaning crab, used by Hippocrates
• Tumor, or neoplasm, refers to new growth from uncontrolled proliferation
• Cancer refers to malignant tumors, not benign growths

Benign Tumors

• Benign tumors are typically encapsulated in connective tissue
• They are made of well-differentiated cells, organized stroma, and retain normal tissue structure
• These tumors do not invade beyond their capsule and don't spread
• Mitotic cells are rare in benign tumors
• Benign tumors use the suffix "-oma," preceded by the tissue of origin
• Polyps, usually in the colon or stomach, and nevi, usually of melanocytes, are examples of benign tumors
• Benign tumors can cause morbidity or be life-threatening by compressing tissue or overproducing hormones

Malignant Tumors

• Malignant tumors grow more rapidly than benign tumors and have microscopic alterations
• They show loss of differentiation (anaplasia) and lack normal tissue organization
• Malignant cells are pleomorphic with variable size and shape
• They commonly have large, darkly stained nuclei, and mitotic cells
• Malignant tumors may have disorganized stroma, lack a capsule, and invade nearby structures
• A key characteristic of malignant tumors is their ability to metastasize

Naming Cancers

• Cancers are usually named after their cell type of origin
• Carcinomas originate in epithelial tissue, with adenocarcinomas forming ductal or glandular structures
• Sarcomas develop from mesenchymal tissue such as connective tissue, muscle, or bone
• Lymphomas are cancers of lymphatic tissue, and leukemias are cancers of blood-forming cells

Carcinoma In Situ (CIS)

• CIS refers to preinvasive epithelial tumors of glandular or squamous cell origin
• They have atypical cells and increased proliferation, but are localized to the epithelium
• They have not penetrated the local basement membrane or invaded the surrounding stroma
• CIS can remain stable, progress to invasive cancers, or regress

Tumor Classification

• Proper cancer identification depends on its causes, progression, spread, and treatment responses
• Classification involves knowing the tissue and organ of origin, distribution extent, microscopic appearance, and genetic changes

Biology of Cancer Cells

• Cancers share hallmarks like sustained proliferation, evading growth suppression, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, deregulating cellular energetics, avoiding immune destruction, promoting tumor inflammation, and genomic instability
• Cancer is a complex genetic disease with a heterogeneous tumor microenvironment of cancerous and benign cells

Genetic Changes in Cancer

• Cancer is a disease of cumulative genetic changes that occur during aging
• These changes happen through mutations and epigenetic mechanisms
• Mutations involve alterations in the DNA sequence
• Epigenetic effects, like DNA methylation and histone modification, can alter gene expression
• Driver mutations "drive" cancer progression, while passenger mutations do not contribute
• A critical number of driver mutations give a selective advantage and clonal proliferation
• Mutation accumulation continues through metastasis progression
• Malignant transformation is fueled by genetic alteration

Tumor Microenvironment

• The tumor microenvironment is important in cancer development
• Cancer cell proliferation triggers proinflammatory mediators, recruiting immune cells and tissue repair cells
• These cells form the stroma that surrounds the tumor
• Paracrine signaling between stromal and cancer cells increases cancer cell proliferation and heterogeneity
• Evolving stromal cells promote cancer progression and metastasis
• Cancer heterogeneity arises from ongoing proliferation and mutation, including cancer stem cells

Sustaining Proliferative Signaling

• Cancer cells mutate pathways that stimulate cell growth
• Oncogenes come from mutated or overexpressed proto-oncogenes and lead to uncontrolled proliferation
• RAS point mutations, N-myc gene amplification, and c-myc/BCR-ABL chromosomal translocations are all alterations that lead to oncogenes
• Cancer cells may secrete their own growth factors or stromal cells may produce excessive growth factors
• Receptor tyrosine kinases (RTKs) like HER2 can sustain proliferative signaling

Evading Growth Suppression

• Normal cells receive antigrowth signals
• Tumor-suppressor genes like RB monitor these signals and block cell cycle progression
• Mutations in tumor-suppressor genes lead to persistent cell growth
• RB inactivation allows uncontrolled cell cycle progression
• The tumor-suppressor gene p53 monitors stress signals and activates DNA repair genes
• Activated p53 can induce senescence or apoptosis if DNA damage is irreparable
• Loss of p53 function is common in cancer
• Inherited loss-of-function mutations in tumor-suppressor genes increase cancer risk
• Familial cancer syndromes are caused by loss of function of tumor-suppressor genes like APC and BRCA1/2

Genomic Instability

• Genomic instability results from defects in DNA repair mechanisms
• This defects lead to an increased rate of mutations
• Inherited disorders impairing DNA repair genes are associated with increased cancer risk
• Genomic instability can also arise from increased epigenetic silencing

Enabling Replicative Immortality

• Normal somatic cells have limited division potential because telomeres shorten with each division
• Cancer cells activate telomerase to rebuild telomeres, allowing indefinite cell division
• Like stem and germ cells, cancer cells can maintain their telomere length
• Cancers can contain cancer stem cells with the capacity for self-renewal and tumor immortality

Inducing Angiogenesis

• Tumors require a blood supply for oxygen and nutrients
• Angiogenesis, or new blood vessel formation, is essential for tumor growth and spread
• Cancer cells increase secretion of angiogenic factors (VEGF, bFGF) and prevent angiogenic inhibitors
• Hypoxia-inducible factor-1α (HIF-1α) regulates angiogenesis and its expression is increased by inactivation of tumor-suppressor genes or increased oncogene expression
• Monocytes, endothelial cells, adipocytes, and cancer-associated fibroblasts also secrete VEGF
• Cancer and stromal cells may increase matrix metalloproteinases (MMPs), which can activate angiogenic factors
• Tumor vessels are abnormal with irregular branching and increased permeability
• Angiogenic inhibitors targeting VEGF signaling can diminish tumor growth

Reprograming Energy Metabolism

• Cancer cells have different nutritional requirements due to their rapid proliferation
• They exhibit aerobic glycolysis (Warburg effect), even with sufficient oxygen
• This generates less ATP but provides metabolic intermediates needed for rapid cell growth
• The reverse Warburg effect suggests cancer cells may induce aerobic glycolysis in cancer-associated fibroblasts
• Oncogenes and mutant tumor suppressors promote aerobic glycolysis
• The high glucose utilization of cancers can be exploited for diagnosis using FDG PET scans

Resisting Apoptotic Cell Death

• Apoptosis, or programmed cell death, eliminates aberrant cells
• The intrinsic pathway monitors cellular stress, and the extrinsic pathway is activated by plasma membrane receptors
• The balance between proapoptotic and anti-apoptotic proteins regulates apoptosis
• TP53 activation by DNA damage can induce proapoptotic factors
• Cancer cells resist apoptosis through loss of p53 function, overexpression of anti-apoptotic molecules, reduced proapoptotic molecules, and inactivated death domain signaling

Promoting Tumor Inflammation

• Chronic inflammation has been recognized as an important factor in cancer development
• Chronic inflammation can result from infections, exposure to irritants, and autoimmune conditions
• Cancers can disrupt the environment and initiate or enhance inflammation
• Tumor-associated macrophages (TAMs) are recruited by cytokines and promote tumor cell proliferation, angiogenesis, and suppression of antitumor immune responses
• Cancer-associated fibroblasts (CAFs) contribute to cancer progression, local spread, and metastasis

Avoiding Immune Destruction

• Many cancers express tumor-associated antigens recognizable by the immune system
• Cancer cells can evade immune destruction through various mechanisms
• Effective immune responses are documented against oncogenic viruses, such as HPV and HBV
• Cancer cells can evade the immune system by losing expression of antigens or MHC molecules
• They produce immunosuppressive cytokines or induce immunosuppressive T-regulatory cells
• Or they express ligands for inhibitory receptors on T cells
• The balance of immune cell types within the tumor can favor tumor growth

Activating Invasion and Metastasis

• Metastasis is the spread of cancer cells to distant tissues and organs and is the major cause of cancer death
• It is a complex and inefficient process involving multiple steps
• Changes in the tumor microenvironment can initiate metastasis
• Epithelial-mesenchymal transition (EMT) is a model for the transition to metastatic cancer cells
• EMT involves a loss of epithelial characteristics and a gain of mesenchymal-like properties
• Invasion involves diminished cell-to-cell adhesion, digestion of the ECM, and increased motility of cancer cells
• Tumor cells often develop resistance to anoikis

Achieving Distant Metastasis

• Cancer cells must invade blood and lymphatic vessels (intravasation)
• They survive in the circulation, extravasate at distant sites, and proliferate to form a new tumor (colonization)
• The pattern of metastasis is determined by the vascular and lymphatic drainage of the primary tumor
• There is selectivity of different cancers for specific metastatic sites
• Establishing a metastatic lesion requires cancer cells to survive in the new environment
• After reaching the metastatic site, tumor cells may undergo a mesenchymal-to-epithelial transition (MET)
• Some metastasized cells may enter a state of dormancy

Clinical Manifestations

• Manifestations of cancer are diverse and depend on the tumor's type and location
• They can result from direct local or distant effects

Paraneoplastic Syndromes

• Paraneoplastic syndromes are symptom complexes triggered by a cancer but not caused by the direct local effects of the tumor mass
• They are caused by biologic substances released from the tumor or by an immune response triggered by the tumor
• Paraneoplastic syndromes can be the earliest symptom of an unknown cancer
• Examples include Cushing syndrome, hypercalcemia, and neurologic disorders

Other Clinical Manifestations

• Pain can occur in early stages but intensifies with progression
• Cachexia is a multiorgan syndrome with decreased energy intake and increased energy expenditure
• Anemia is common, caused by chronic bleeding, malnutrition, chemotherapy, and malignancy
• Fatigue is the most frequently reported and persistent symptom
• Chemotherapy and radiation can damage GI cells, leading to oral ulcers, malabsorption, and diarrhea
• Chemotherapy affects hair follicles, and decreased skin renewal can lead to breakdown and dryness
• Infection is the most significant cause of complications and death, due to immune suppression
• Lymphedema can result from obstruction of the lymphatic system

Diagnosis and Staging

• Diagnosis of cancer requires examination of tumor tissue by a pathologist
• Tissue can be obtained through biopsy procedures
• Cancer staging determines if the cancer has spread, initially involving tumor size (T), local invasion, lymph node spread (N), and distant metastasis (M)
• A four-stage system is generally used, with carcinoma in situ as a special case
• Stage 1 is cancer confined to the organ of origin, stage 2 is locally invasive, stage 3 has spread to regional structures, and stage 4 has spread to distant sites
• The TNM system is a standard staging scheme
• Specific molecular tests are increasingly used in staging
• Tumor markers are biochemical substances produced by benign and malignant cells
• They include hormones, enzymes, genes, antigens, and antibodies
• They can be used to screen high-risk individuals, diagnose tumor types, and follow the clinical course
• No single tumor marker is satisfactory for general population screening
• Immunohistochemical and genetic analysis is important for cancer classification and treatment decisions
• Classification now includes immunohistochemical analysis of protein expression and more extensive genetic analysis of tumors
• Global gene expression and mutation analysis can classify tumors more precisely and predict therapy response

Treatment

• Treatment has evolved, with classic approaches including surgery, radiation, and chemotherapy
• Newer approaches include immunotherapy and targeted therapies

Classic Approaches

• Surgery is used for diagnosis, staging, prevention, and treatment
• Radiation therapy damages DNA and kills cancer cells
• Chemotherapy attacks pathways in rapidly dividing cells and has induction, adjuvant, or neoadjuvant purposes
• Side effects of Chemotherapy includes bone marrow suppression, leading to anemia, leukopenia, and thrombocytopenia, which can be managed with supportive therapies

Immunotherapy

• Immunotherapy initiates or boosts an immune response against cancer cells
• Genetic engineering of T cells express chimeric antigen receptors (CARs) that target tumor antigens
• Cancer vaccines stimulate the immune system to recognize and attack cancer cells
• Passive immunotherapy involves administering tumor-targeting lymphocytes
• Cytokines enhance T-cell and NK cell activity
• Monoclonal antibodies bind to and damage cancer cells
• Immune checkpoint inhibitors block costimulatory molecules that repress T-cell immune responses

Targeted Disruption

• Cancer treatment include drugs that specifically target molecular abnormalities
• Combining drugs targeting multiple cancer hallmarks is increasingly efficacious
• Modern cancer therapy analyzes individual cancers to determine the optimal combination of therapies

Prevention

• Cancer prevention includes lifestyle changes, reducing exposure to air pollution, occupational hazards, synthetic chemicals, sunlight, and ionizing radiation