Neoplasia and Metastasis PDF

Neoplasia and Metastasis B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Learning Outcomes • Define neoplasia and differentiate between benign and malignant neoplasms. • Describe the genetic and environmental factors that contribute to neoplasia. • Expl...

Neoplasia and Metastasis B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Learning Outcomes • Define neoplasia and differentiate between benign and malignant neoplasms. • Describe the genetic and environmental factors that contribute to neoplasia. • Explain the molecular mechanisms of metastasis including immune evasion. Basic components of a tumour • Clonal expansions of neoplastic cells constituting the tumour parenchyma. • Supporting stroma composed of non -neoplastic connective tissue, blood vessels and variable numbers of cells of the adaptive and innate immune system. • Abundant collagenous stroma is called desmoplasia, and such tumours will be rock hard or scirrhous. Morphological Characteristics Characteristics Benign Malignant Differentiation or anaplasia Well differentiated; structure sometimes typical of tissue of origin Some lack of differentiation (anaplasia); structure often atypical Rate of growth Usually progressive and slow; may come to a standstill or regress; mitotic figures rare and normal. Erratic, may be slow to rapid; mitotic figures may be numerous and abnormal. Local invasion Usually cohesive, expansile, well -demarcated masses that do not invade or infiltrate surrounding normal tissues Locally invasive, infiltrating surrounding tissue; sometimes may be misleadingly cohesive and expansile Metastasis Absent Frequent; more likely with large undifferentiated primary tumours Molecular mechanisms of neoplasia • Neoplasia is driven by alterations in the molecular pathways that regulate cell growth and division. • Oncogenes are genes that promote cell growth and division when mutated or overexpressed. • Tumour suppressor genes are genes that normally prevent cell growth and division but become inactive when mutated. • Other molecular pathways that contribute to neoplasia include DNA damage and repair pathways, apoptosis and cell death pathways, and epigenetic modifications. Metaplasia • A process in which one differentiated cell type is replaced by another due to tissue damage, repair, and regeneration. It is reversible and does not involve intrinsic gene defects. • However, because the metaplastic tissues are less genetically stable than their normal counterparts, they may undergo further transformation to dysplasia and neoplasia. • For example, gastroesophageal reflux can damage the squamous epithelium of the oesophagus, leading to its replacement by glandular (gastric) epithelium. • See Barrett’s oesophagus (Semester 1, Lecture 8, Slide 8 -9) Dysplasia • A failure of normal maturation that occurs prior to the development of malignancy and is often irreversible. • It is more easily recognised in epithelial tissues than in other tissues. • Dysplasia may be preceded by metaplasia. When dysplastic changes involve the entire thickness of an epithelium, it is considered a preinvasive neoplasm known as carcinoma in situ. • Once the tumour cells breach the basement membrane, the tumour is considered invasive. Local invasion - Benign • Nearly all benign tumours grow as cohesive expansile masses that remain localized to their site of origin. • Benign tumours grow and expand slowly, they usually develop a rim of compressed fibrous tissue called a capsule that separates them from the host tissue. Local invasion - Malignant • Malignant neoplasms are typically invasive and infiltrative, destroying surrounding normal tissues. • They commonly lack a well -defined capsule and cleavage plane, making simple excision impossible. • Surgery requires removal of a considerable margin of healthy and apparently uninvolved tissue. Metastasis • Secondary growth of a neoplasm at one or more locations distant from the primary site, and it is the most important feature distinguishing benign from malignant tumours . • Different from cancer invasion, which is the direct extension and penetration by cancer cells into neighbouring tissues. • Spread of cancer may occur through lymphatics, blood vessels, across coelomic cavities, within cerebrospinal fluid, or through implantation of neoplastic cells following biopsy or surgery. • Almost all malignant tumours can metastasize, but central nervous system tumours and cutaneous basal cell carcinomas do so only rarely. Signs and symptoms The lungs, liver, brain, and bones are the most common metastasis locations from solid tumours. • Lymph node metastasis: a common symptom is lymphadenopathy • Lung metastasis: cough, haemoptysis and dyspnoea (shortness of breath) • Liver metastasis: hepatomegaly (enlarged liver), nausea and jaundice • Bone metastasis: bone pain, fracture of affected bones • Brain metastasis: neurological symptoms such as headaches, seizures, and vertigo Although advanced cancer may cause pain, it is often not the first symptom. Seeding of body cavities and surfaces • Seeding can occur when a malignant tumour penetrates a natural "open field" that lacks physical barriers. • This most commonly occurs in the peritoneal cavity but can also occur in other cavities such as the pleural, pericardial, subarachnoid, and joint spaces. • In the peritoneal cavity, cancer can spread from one organ to another, such as carcinoma of the stomach spreading to the ovary. • In the pleural cavity, a primary lung cancer can spread to the pleura of the other lung. Lymphatic spread • The lymphatic system transports tumour cells from the primary tumour site to regional nodes and ultimately throughout the body. • Lymph nodes draining tumours are frequently enlarged due to either metastatic tumour cell proliferation or reactive hyperplasia to tumour antigens. • Biopsy of the proximal sentinel lymph node draining a tumour can allow for accurate assessment of tumour metastasis. Sentinel lymph node • the first lymph node to which cancer cells are most likely to spread from a primary tumour . • A sentinel lymph node biopsy is a procedure in which the sentinel lymph node is identified, removed, and examined to determine whether cancer cells are present. • This technique is often used to determine the extent of cancer spread in early -stage cancers and to inform treatment decisions. • See also “Molecular Diagnostics” (Semester 1, Lecture 5, Slide 27 -28). Hematogenous spread • Common in sarcomas and some carcinomas. • Veins are more commonly invaded than arteries due to their thinner walls, and the spread of metastases generally follows the pattern of venous flow. • The lung and liver are the most frequently affected sites of hematogenous metastases. • Some cancers tend to spread to specific organs as they have tissue -specific homing receptors (organ tropism). Mechanism of invasion and metastasis 1. Detachment of neoplastic cells from the tumour 2. Attachment to extracellular matrix (ECM) 3. Degradation of the ECM 4. Locomotion through the ECM 5. Vascular intravasation 6. Interaction of tumour cells with host lymphocytes 7. Formation of tumour embolus 8. Adhesion to endothelium at a distant site 9. Vascular extravasation 10. Regrowth of the metastatic clone Invasion of ECM • E-cadherins are glycoproteins that enable the adhesion of epithelial cells to each other and allow intercellular signalling . • When E -cadherin is downregulated, cells lose their ability to adhere to one another, which can facilitate detachment from the primary tumour . Degradation of ECM • Tumours produce proteases or stimulate stromal cells to produce them, including matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator. • MMPs degrade type IV collagen of the epithelial and vascular basement membrane, releasing growth factors such as VEGF. Migration and invasion • Loss of adhesion in normal cells leads to induction of apoptosis, tumour cells are resistant to this form of cell death • Tumour cell -derived cytokines, cleavage products of matrix components, and paracrine effectors of cell motility produced by stromal cells stimulate and direct tumour cell movement • Stromal cells that interact with tumours include innate and adaptive immune cells, as well as fibroblasts Vascular dissemination and homing • Tumor cells embolize in the bloodstream as self -aggregates and by adhering to circulating leukocytes and platelets. • Exactly where tumor cell emboli eventually lodge and begin growing is influenced by the following: • Vascular and lymphatic drainage from the site of the primary tumor. • Interaction with specific receptors. • The microenvironment of the organ or site. Organ t ropism May be related to the following: • Adhesion molecules, whose ligands are expressed on the endothelial cells of the target organ. • Chemokines , these have an important role in determining the target tissues for metastasis. • e.g. breast cancer cells expressing the protein CXCR4 tend to metastasize to organs that produce high levels of its ligand, CXCL12, such as lung, liver, and bone. • Target tissue may be a nonpermissive environment (“unfavorable soil”) • e.g. skeletal muscle and spleen are rarely sites of metastasis. Why do only some tumours metastasize? Tumours with genetic mutations may have increased ability to invade and migrate: • Some tumours produce enzymes to degrade extracellular matrix, allowing migration • Mutations in cell adhesion genes can promote detachment and migration • Mutations in cell signalling or DNA repair genes help tumours adapt to new environments • Genetic instability can lead to accumulation of mutations and new abilities • Abilities may include evading immune system or resisting chemotherapy Metastasis oncogenes Oncogenes : Genes that can potentially cause cancer when mutated or expressed at high levels (Normal counterparts: Proto -oncogenes, which regulate cell growth and division) Metastasis Oncogenes : Specific oncogenes that drive the metastatic process • Encourage cell migration, invasion, and survival in new environments • Examples: RAS family (KRAS, NRAS, HRAS), MYC, MET Implications for cancer treatment: • Targeted therapies against metastasis oncogenes • Personalized medicine based on individual tumour's genetic profile Evasion of host defense • Downregulation of tumour antigens • Loss or reduced expression of MHC molecules • Upregulation of immune checkpoint molecules • e.g., CTLA -4 and P D -L1 • Secretion of immunosuppressive factors • e.g., TGF -β , IL -10, PGE2, IDO • Recruitment of immunosuppressive cel ls • e.g., Tregs, MDSCs, TAMs Key immune checkpoint molecules PD -L1 (Programmed Death -Ligand 1): Cancer cells can upregulate the expression of PD -L1 on their surface, which binds to PD -1 on T cells, inhibiting T cell activation and promoting immune tolerance. CTLA -4 (Cytotoxic T -Lymphocyte -Associated Protein 4): This molecule is expressed on T cells and competes with the co -stimulatory molecule CD28 for binding to B7 family ligands (CD80/CD86) on antigen -presenting cells. When CTLA -4 binds to these ligands, it delivers inhibitory signals to T cells, dampening their activation. GLOSSARY Immunosuppressive factors Transforming Growth Factor -beta (TGF -β): A multifunctional cytokine that suppresses immune cell activity and proliferation, and promotes differentiation of Tregs, contributing to tumour immunosuppression. Interleukin -10 (IL -10): An anti -inflammatory cytokine that inhibits immune cell function and activation, promotes Treg differentiation, and suppresses pro -inflammatory cytokine production. Prostaglandin E2 (PGE2): A lipid mediator that suppresses immune cell activity, and promotes the expansion of Tregs and MDSCs, further contributing to tumour immunosuppression. Indoleamine 2,3 -dioxygenase (IDO): An enzyme that produces immunosuppressive metabolites, inhibits T cell activation and proliferation, promotes Treg differentiation, and suppresses NK cell and dendritic cell function. GLOSSARY Key immunosuppressive cells Regulatory T cells (Tregs): Maintain immune tolerance but can suppress anti -tumour immune responses in the tumour microenvironment; recruited by cancer -secreted chemokines and cytokines (e.g., CCL22, TGF -β). Myeloid -derived suppressor cells (MDSCs): Immature myeloid cells that inhibit the function of various immune cells; attracted to the tumour microenvironment by cancer -released factors (e.g., GM -CSF, IL -6). Tumour -associated macrophages (TAMs): Macrophages with an immunosuppressive phenotype in the tumour microenvironment; inhibit immune responses, promote tumour growth, and facilitate angiogenesis; recruited by cancer -secreted chemokines (e.g., CCL2). GLOSSARY Approaches to counter immune evasion Immune checkpoint inhibitors: • Block immune -suppressive signals (e.g., PD -L1, CTLA -4) • Restore anti -tumour immune responses Targeting immunosuppressive factors: • Neutralize cytokines (e.g., TGF -β, IL -10) • Inhibit enzymes (e.g., IDO) Disrupting immunosuppressive cell recruitment: • Target chemokines and cytokines (e.g., CCL22, GM -CSF) • Reprogram or deplete immunosuppressive cells (e.g., Tregs, TAMs) Cancer vaccines: • Boost immune response against tumour antigens • Personalized based on tumour profile Adoptive T -cell therapy: • Transfer engineered immune cells (e.g., CAR -T cells, TCR -T cells) • Enhance immune cell function and specificity Why do patients die from neoplasia? 1. Widespread disease in multiple organ sites (carcinomatosis ) 2. Metastatic disease in vital sites such as the brain, lung or heart 3. Immunosuppression, either due to the neoplasm or to chemotherapy, leading to opportunistic infections 4. Organ failure 5. Haemorrhage exacerbated by anaemia and thrombocytopenia 6. Late second malignancies, either due to inherited genetic abnormalities in the patient or to the effects of previous therapy.