Tumor Progression and Metastasis Flashcards
Tumor Progression
- Loosening of intercellular junctions; cancer cells losing their ability to maintain normal communication network from cell to cell- cells losing contact inhibition which enables cells to communicate w/ one another and for the cell to remain stable
- Attachment; cancer cells start forming more specific contacts w/ the basement membrane, especially if these cells are laying on that basement membrane- they start expressing receptors for some of these basement membrane proteins (Laminin receptor, Fibronectin receptor)
- Degradation; cells are starting to make enzymes- gene mutations allowing for metastatic capabilities, meaning that the mutations are creating certain proteins that allow for degradation of surrounding environment (Type IV collagenase)
- Migration; cancer cell going through the basement membrane- can have autocrine motility factors that are being made by these metastatic cells- not all are metastatic at first; some are getting the mutation
Tumor angiogenesis
- Tumors cannot enlarge beyond 1-2 mm w/o being vascularized
- FGF
- VEGF
- Angiogenesis aid in tumor metastasis
Flowchart depicting a simplified scheme of the molecular basis of cancer
Mechanisms of metastasis development within a primary tumor
Invasion of ECM
1- Detachment of tumor cells
2- Attachment of tumor cells to matrix
3- Degradation of ECM
4- Migration of tumor cells
Metastasis Meaning
- Denotes the development of secondary implants discontinuous w/ the primary tumor
Modes of Metastasis
- Lymphatic
- Haematogenous
- Retrograde
- Transcoelomic
Lymphatic Spread
- Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas
- Sarcomas may also use this route
Retrograde Metastasis
- Due to obstruction of the lymphatics by the tumor cells the lymph flow is disturbed and tumor cells spread against the flow of lymph causing retrograde metastasis
- Examples: Cancer of the prostate to the supraclavicular lymph nodes and metastatic deposits from bronchogenic cancer to axillary lymph nodes
Virchows lymph nodes
- Nodal metastasis preferentially to the left supraclavicular lymph nodes from cancers of abdominal organs (e.g. cancers of stomach, colon and gallbladder)
Pattern of Lymph Node Involvement During Metastasis
- Follows the natural routes of lymphatic drainage
- Carcinomas in the upper outer breast quadrants disseminate first to the axillary lymph nodes
- Carcinomas of the inner quadrants drain to the nodes along the internal mammary arteries thereafter to the infraclavicular and supraclavicular nodes
- Regional lymph nodes draining the tumor are invariably involved leading to regional nodal metastasis
*carcinoma of the breast to axillary lymph noes
*carcinoma of the thyroid to lateral cervical lymph nodes
*bronchogenic carcinoma to hilar and paratracheal lymph nodes
Skip Metastasis
- When local lymph nodes are bypassed b/c of venous-lymphatic anastomoses or inflammation or radiation has obliterated the lymphatic drainage
Hematogenous spread
- Typical of sarcomas but is also seen w/ carcinomas. Arteries, w/ their thicker walls, are less readily penetrated than are veins
- Arterial spread may occur, however, when tumor cells pass through the pulmonary capillary beds
Metastatic Cascade: Steps Involved in the Hematogenous spread of a tumor
- Liver and lungs are most frequently involved in hematogenous dissemination
*reason: all portal area drainage flows to the liver, all caval blood flows to the lungs
Common and Uncommon Sites of Blood Borne Metastasis
- Liver, lungs, brain, bone, kidney, adrenals
- Spleen, heart, skeletal muscles do not allow tumor metastasis to grow
- Spleen is unfavourable site due to open sinusoidal pattern which does not allow tumor cells to metastasize
- Limbs, head, neck and pelvis drain blood via vena cava so cancers from these sites metastasize to lungs
Certain Cancers with a Propensity for Invasion of Veins
- Renal cell carcinoma- often invades the branches of the renal vein and then the renal vein itself to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart
- Hepatocellular carcinomas- often penetrate portal and hepatic radicles to grow within them into the main venous channels
Transcoelomic Spread
- Carcinoma of stomach seeding both the ovaries (Krukenberg tumor)
- Carcinoma of the ovary spreading to entire peritoneal cavity w/o infiltrating the underlying structures
- Pseudomyxoma peritonei is the gelatinous coating of the peritoneum from mucin secreting carcinoma of the ovary or appendix
Carcinoma of Bronchus and Breast Seeding
- Seeding to the pleura and pericardium
- Spread along epithelial lined surfaces
*through fallopian tube from endometrium to ovaries vice versa
*through bronchus to alveoli
*through uterus from kidney into lower urinary tract
- Spread via cerebrospinal fluid in the nervous system
Effects of Tumors
- Local effects: local destruction of tissues causes loss of function, ulceration, hemorrhage, obstruction
- Hormone production: well differentiated (benign) tumors of endocrine glands may secrete hormones and cause hyperfunction
Cancer Cachexia
- i.e. wasting and weakness. May be due to loss of appetite, and production of TNF-alpha (cachectin) and possibly other factors by tumor cells and by reactive macrophages
Diseases Assoc. w/ Prolonged Asbestos Exposure
- Asbestosis (extensive interstital pulmonary fibrosis)
- Non-neoplastic pleural disease
*visceral pleural fibrosis
*round atelectasis
*pleural plaque formation
*pleural effusion
- Malignant mesothelioma
- Bronchogenic carcinoma (lung cancer)
Chemical Carcinogens
- Direct acting agents: require no metabolic conversion to become carcinogenic
- Indirect acting agents: require conversion
*aromatic hydrocarbons: cigarette smoke
*aromatic amines and azo dyes
- Result in gene mutations
General Schema of Events in Chemical Carcinogens
Radiation Carcinogenesis
- UV rays: melanoma, basal cell carcinoma and squamous cell carcinoma
- Causes chromosome breakage, translocations and point mutations
Four Main Oncogenic DNA viruses
- Human Papillomavirs (HPV)
- Epstein-Barr Virus (EBV)
- Hepatitis B virus (HBV)
- Kaposi Sarcoma Virus (KSHV)
DNA Virus Characteristics
- Transforming viruses
*stable assoc. w/ host genome
*viral genes transcribed early in life
*life cycle is important (e.g., latency)
HPV Mechanism of Cancer
- 50-75% of infections- high risk subtypes: HPV 16, 18, 31, 33, 35
*high grade cervical dysplasia more common in women >35
*over 99% of cervical cancers have HPV DNA detected within the tumor
- Integration of DNA into host genome causes transformation
- Viral DNA always disrupted at the same site (E1/E2 open reading frame)
*E2 usually represses early genes E6 and E7
- E1/E2 split causes overexpression of E6 and E7 proteins of HPV16 and 18
- Oncogenic potential due to E6 and E7
*E6 binds p53 tumor suppressor protein- results in degradation
*E7 binds to pRb tumor suppressor protein- result in unbinding of E2F transcription factor
Epstein-Barr Virus Mechanism of Cancer
- Four types of cancers
*Burkitt’s lymphoma
*B-cell lymphoma in immunosuppression
*Hodgkin’s disease
*Nasopharyngeal carcinoma
- Cell tropism determine by presence of EBV receptor
- Binds CR2 or CD21 (receptor for C3b, component of C’) on B cells and epithelial cells of the oropharynx and nasopharynx
*MHC class II molecules are used as co-receptors
- Linear genome forms circular episome in nucleus- a laten infection (no viral replication and no cell death)
- B cells- immortalized and propagate
- Some immediate early genes are expressed
*Epstein-Barr nuclear antigens (EBNAs)
*Latent proteins (LP)
*Latent membrane proteins (LMP)
*2 small Epstein-Barr-encoded RNA molecules (EBER)
- Viral proteins lead to dysregulation
- LMP-1-antiapoptotic with increased bcl-2 and activates growth promoting pathways
- EBV- encoded EBNA-2 gene- transactivates host genes such as cyclin D and src and even activates the viral LMP-1 gene
Immortalization of B cells by EBV
- Cells are stimulated to divide and secrete antibody
*polyclonal activation
*heterophile antibodies
+IgM which recognizes antigens on sheep, horse and bovine erythrocytes
- EBV-activated B cells are eliminated by T cells
*activation and proliferation of T cells produces mononucleosis
*lack of T cell control may result in a lymphoma
Kaposi Sarcoma Herpesvirus (HHV8) Mechanism of Cancer
- Infects B cells, vascular endothelial cells, perivascular spindle cells and others
- Virus expresses proteins w/ homology to cellular proteins that promote growth and inhibit apoptosis
- Encodes homologs of human proteins important for cell proliferation
*IL-6 (mitogen for spindle cells in lesions)
*bcl-2 (anti-apoptotic protein)
*cyclin D (regulates cell cycle G1-S phase)
- KS cells secrete TNFa, IL-1, IL-6, GM-CSF, bFGF
Hepatitis B Virus Mechanism of Cancer
- Integrated into host genome- tumors are clonal
*NOTE: no oncoprotein is coded, no insertion near known protooncogens
- Encodes a regulatory protein called Hbx
*disrupts growth control- activates insulin-like growth factor II gene and receptors for this
*bind p53- inhibits apoptosis
