Cancer Flashcards
Properties of Cancer
- uncontrolled growth
- invasion and metastasis
- clonal dominance
- loss of differentiation
Mutant subclones are heterogeneous with respect to…
- invasiveness
- metastatic ability
- antigenicity
- responsiveness to chemotherapy
Types of cancer therapy
- surgery
- radiotherapy
- chemotherapy
- immunotherapy
limitations in treating cancer
- lack of tumor specific antigen
- tumor cell heterogeneity
micrometastasis
What are the causes of human cancer
- environmental carcinogens
- UV radiation
- other ionizing radiation
- virus
- lifestyle, diet, immune status
- hereditary factors or genes
- unknown
ionizing and uv radiation can cause…
chromosome breakage, translocations and point mutations
Radiation differs from chemical carcinogens in that…
chemical carcinogens cause single stranded DNA adducts, radiation can cause both single and double stranded DNA breaks
DNA oncogenic viruses
- HPV
- Epstein- Barr virus
- Hep B Virus
malignant types of HPV
16 and 18 are found in almost 100% of invasive squamous cell carcinoma and carcinoma in situ of cervix
which early gene products in HPV cause tumors
E6- inactivates tumor suppressor TP53
E7- inactivates tumor suppressor RB
Tumors associated with EBV
- Burkitt’s Lymphoma (all associated with t(8:14)-MYC gene
- B cell lymphoma in immune compromised (AIDS)
- Hodgkin’s Disease
- Nasopharyngeal Cancer
Hepatitis B virus is associated with…
Hepatocellular cancer. injury and regeneration predispose to mutations with environmental genes
Role of HBx-protein in hepatocellular cancer
disrupts growth control by activating protooncogenes, may inactivate TP53
lifestyle mechanisms of cancer (4)
- sun bathers have increased risk skin cancer
- promiscuous women have increased risk of cervical cancer
- nulliparous women have increased risk of breast cancer
- obese men have increased risk of esophageal cancer
diet mechanisms of cancer (3)
- women who eat fatty food have increased risk of breast cancer
- men who smoke and drink have increased risk of head and neck cancer
- people who eat red meat have increased risk of colon cancer
Hereditary factors or genes
- P53 - Li-Fraumani syndrome
- BRCA1 and BRCA2 - breast cancer
- Lynch Syndrome and microsatelite instability genes
- inherited RB
two key properties of cancer
- property of uncontrolled growth
2. property of invasion and metastasis
what are Oncogenes
genes that code for products (oncoproteins) associated with neoplastic formation. these are not regulated by normal growth factors or signals.
what are Protooncogenes
normal genes that affect growth and differentiation. retroviral transduction (v-onc), where changes in situ convert to c-onc
Activation of oncogenes (protooncogenes to oncogenes) (3)
- point mutations- RAS most common
- chromosomal translocation- moved near promoter or chimeric gene product
- gene amplification- N-MYC in neuroblastoma, HER-2 in breast cancer
5 basic categories of oncogenes
- growth factors
- growth factor receptors
- signal transducing proteins
- nuclear transcription factors
- cyclins and cyclin dependent kinases
cancer suppressor genes (antioncogenes)
cancer can be promoted due to inactivation of genes who’s products suppress cell proliferation.
- growth inhibatory factors
- molecules that regulate cell adhesion
- molecules that regulate signal tranduction
- molecules that regulate nuclear transcription and cell cycle
role of TP53
senses DNA damage, arresting cell in G1 of cell cycle and inducing DNA repair.
it increases CDK1 p21 (CDKN1A), preventing phosphorylation of RB.
It induces GADD45, which aids in DNA repair
Li-Fraumani Syndrome
inherit one mutant TP53 or RB, leading to market increased risk in multiple types of malignancies. still requires mutation of the second normal allele.
can be inactivated by certain DNA viruses like oncogenic HPV, HBV, and possibly EBV
Retinablastoma Gene (RB)
assocaited with childhood retinoblastoma. two hit hypothesis states that two normal RB loci requires both genes to be inactivated by somatic mutation. familial cases with only one normal gene only need one hit, leading to increased risk of sarcomas, including osteosarcomas.
Epigenetic role in cancer
many cancer genes are regulated epigenetically. methylation status and histone deacytylase status with in promoters regulate gene expression at key cancer genes. cancer is characterized by METHYLATION AND HISTONE DEACYTYLATION IMBALANCE
Definition of Cancer Invasion
active migration of neoplastic cells out of their tissue origins and across host tissue boundaries
definition of metastasis
- a secondary tumor colony discontinuous from the primary tumor
- arising from a tumor cell translocated from the primary tumor
3 main routes of malignant neoplasm metastasis
- lymphatic spread (regional lymph nodes usually first)
- hematogenous spread (lung, liver, brain, bone marrow, adrenals)
- transcoelomic spread/ seeding of body cavities (peritoneal, pleural, pericardial, subarachnoid spaces)
Grading of cancer
microscopic, I-IV
well, moderately, poorly differentiated, undifferentiated
Staging of cancer
TNM- Tumor, lymph Node, Metastasis
Tumor: 0-3, with three being through basement membrane
Nodes: 0-2. 0 is no nodes, 1 is local nodes, 2 is distant nodes
Metastases: 0, 1, X. O none, 1 in liver, X in lung, liver, bone
Steps of metastasis (5)
- cells must become less cohesive (ex, E-cadherins decrease)
- attachment to matrix components (laminin and fibronectin)
- degredation of extracellular matrix (metalloproteinases-collagenases and plasmin)
- migration (cytokines and cleavage products of ECM)
- vascular dissemination and homing of tumor cells. may travel as emboli with leukocytes and platelets or as single cells.
types of stem cells
- embryonic stem cells
- induced pluripotent stem cells
- adult (somatic) stem cells
- stem cells in tissue homeostasis
- cancer stem cells
essential properties of all stem cells
- self renewal
- symmetrical and asymmetrical cell division
- pluripotency
properties of CANCER stem cells
- exist in resting or dormant state
- resist chemotherapy and radiotherapy
- express embryonic stem cell pathways
- replenish the dividing cell population of the tumor
pathways involved in stem cell self renewal
- hedgehog
- Notch
- Bmi-1
- Wnt
- Pten
why do tumor remission or response rates not correlate to overall survival
tumor regression may be a reflection of destroying the proliferating population of the tumor, but may not indicate the status of the stem cell fraction that can cause recurrences
4 types of biomarkers
- tumor markers
- prognostic markers
- predictive markers
- surrogate end point markers
Paraneoplastic syndrome examples
May be first sign of malignancy.
- Cushings syndrome: ACTH or ACTH like substance
- -small cell CA of lung, pancreatic CA, neuronal tumors - venous thrombosis: Trosseau’s phenomenon
- -pancreatic, lung, other - hypercalcemia: PTHrP, TGF alpha
- -breast, renal, squamous cell cancer - hypertrophic osteoarthopathy and clubbing of fingers
- -lung cancer
Cachexia
weight loss, weakness, anorexia, anemia. increased metabolic rate despite decreased caloric intake causes weight loss and muscle breakdown. thought to be due to TNF alpha (aka cachexin) and other cytokines
Tumor markers
- paraneoplastic syndromes
- cachexia
- serum biochemical analysis
examples of prognostic markers
info of disease prognosis.
- Estrogen receptor in breast cancer
- Ki-67 in breast cancer
- microsatellite instability gene products in colon cancer
- p21 and p27 in prostate cancer
- p53 in bladder cancer
Surrogate End Point Markers
give info into the effectiveness of chemopreventative or therapeutic strategy before direct tumoral measurement can be assigned
