CCHM TUMOR MARKERS Flashcards
Major Processes Involved in Cell Growth
Proliferation
Differentiation
Formation of solid mass or tumor
Activation of ___ eg. ___
Activation of ____ (___),
Inhibition of ____, ___ and ____ (eg___)
Tumorigenesis
- growth factors (e.g., epidermal growth factor [EGF])
- oncogenes e.g., K-ras
-apoptosis
- tumor suppressor
cell cycle regulation genes (e.g., BRCA1, p53, cyclins)
Involves the multiplication of cells in an organ or tissue, which may consequently have _____ in volume.
Serves a useful purpose and is controlled by ____
Elevation of tumor markers is _____.
Hyperplasia
-increased
- stimuli
- transient
Tumors remain at the primary site and present a smaller risk to the host
At this stage the patient stands a good chance of being successfully treated by the complete removal of the tumor.
Early detection is critical to ___ prevention in general to high risk families in particular
Well differentiated and composed of cells resembling the nature of normal cells from the tissue of origin of the ____.
Benign
- cancer
- neoplasm
Involves the possibility of normal cells undergoing cancerous proliferation
Pathologic hyperplasia
Unregulated and serves no purpose
Elevation of tumor markers will be a___ phenomenon if not treated
Neoplasia
- long lasting
Due to genetic instability of tumor cells.
Malignant
____ malignancy that begins in the skin or in tissues that line or cover internal organs
Carcinoma
malignancy that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue
Sarcoma
malignancy that begins in blood-forming tissue, such as the ___> causes too many abnormal blood cells to be made
Leukemia
- bone marrow
malignancies that begin in the cells of the immune system
Lymphoma and multiple myeloma
refers to the uncontrolled growth of cells that can develop into a solid mass or tumor and spread to other areas of the body
cancer
Cause of the most cancer deaths
Due to multiple genetic changes that result to uncontrolled proliferation
Multistep processes involving numerous tumor cell-host cell and cell-matrix interactions
___ at the primary site penetrate their adjacent surroundings (epithelial basement membrane and the interstitial stroma.)
> invade ____ or ____ to distant sites
> venous/capillary beds or solid tissue of a distant organ.
It is a ___ selective process.
Metastasis
- Tumor cells
- blood or lymphatic vessels
- highly
Controls both ___ and __
Orderly and specific transmission of growth-regulatory messages from outside the cell to the machinery controlling replication inside the cell nucleus.
Signal Transduction Pathway
cell cycle and apoptosis
It involves the passage of a cell through a complete round of ___.
It is one of the most important determining factors controlling cell proliferation.
Cell Cycle
- replication
In most mammalian cells, the cell cycle is composed of ____, ___, ____, and ___
four phases:
G1, S, G2, M or Mitosis, Go
defined as the interval between the conclusion of mitosis and start of DNA replication
G1
– interval during which the nuclear genome is replicated
s
interval between completion of DNA replication and the onset of mitosis.
G2
fifth phase – metabolic compartment of reversibly quiescent cells occupy
Go
Encoded by a separate category of genes when mutated, will not only increase genetic instability but also ____ cellular evolution and the progression to ___.
___ is result from the absence of certain cell cycle controls
Defects in the cell cycle machinery may help cause ___.
Cell Cycle
- accelerate
- malignancy
- Tumors
- cancer
A programmed cell or physiologic death
It is a natural self-destruct system present in all cells
Failure of cells to undergo ____ may lead to cancer.
It is the natural process the body replacement of cells and the deletion of damaged cells inherent to normal functioning of multicellular microorganism.
Apoptosis
- apoptotic cell death
It is a control mechanism for _____ and ___
Provides a way for the body to eliminate cells that have been produced in excess, that have developed improperly, or that have sustained genetic damage.
Apoptosis
tissue remodeling during growth development.
Apoptosis Markers: ____, ___, and ____
They can be both inducers and inhibitors of cell-death
These markers would have tremendous potential for ___, ____ and ___
p53 protein, Bcl 2, and Fas/Fas ligand
diagnosis,
prognosis
therapeutic application
New blood vessels are formed. Tumor growth and metastasis are _____.
It is critical, not only for the growth of solid tumors, but also for the shedding of cells from the primary tumor and the development of metastases at distant sites.
The new blood vessels embedded in a tumor provide a gateway for tumor cells to enter the circulation and to metastasize to distant sites
Angiogenesis
- angiogenesis-dependent
The degree of it is an initial primary tumor correlates with metastatic spread and survival rates in patients
Assessment may, therefore, prove valuable in selecting patients with ___for aggressive therapy.
Angiogenesis
- early breast carcinoma
Most well known angiogenic factors:
___, ___ and ___
Vascular endothelial growth factor (VEGF)
Acidic and basic fibroblast growth factor (aFGF and bFGF)
Transforming growth factor alpha (TGF-alpha)
These are specific class of transmembrane glycoprotein involved whenever cells are ____ and __
They regulate the migration of ___ to sites of inflammation or into lymphatic tissue
Adhesion
-moving
- interacting
- leukocytes
Increasing evidence has shown that the appearance of certain membrane molecules is related to metastatic potential or a sign of the conversion of normal to ___
Adhesion
- malignant cells.
Three classes of adhesions:
___, ___ and ___
Selectins
Integrins
Immunoglobulin family
Cancer Progression
Metastasis
Loss of cell adhesion proteins (e.g., β-catenin and E-cadherin)
Activation of angiogenesis genes (e.g., VEGF)
Cancer Progression
Activation of oncogenes
Upregulation of proteases
Deactivation of adhesion molecules
Stimulation of angiogenesis genes
Mutation of cell cycle and DNA repair genes
Loss of tumor suppressor genes
Growth factor dysregulation
Activation of oncogenes
Ras proteins
Upregulation of proteases
MMPs Matrix metalloproteinases
Deactivation of adhesion molecules
E-cadherin
Stimulation of angiogenesis genes
VEGF Vascular endothelial growth factor (VEGF)
Mutation of cell cycle and DNA repair genes
p53, BRCA1, Cyclins
Loss of tumor suppressor genes
pRb APC
Growth factor dysregulation
EGF Epidermal growth factor (
HER2/neu
Factors Considered in Cancer Severity
Tumor size
Histology
Regional lymph
Node involvement
Presence of metastasis
higher stages are indicative of significant spreading and severe systemic disease
Disease severity
proliferation and metastasis occur at the expense of normal organ processes cause of morbidity and mortality
Disease Progression
Localized primary tumor
stage I
Invasion of primary tumor through epithelium and into blood vessels
stage II
Migration of tumor into regional lymph nodes
Stage III
Metastasis and invasion of tumor to distant tissues
stage IIII
Produced either directly by the tumor or as an effect of the tumor on healthy tissue (host)
Tumor Markers
Tumor markers used to
Differentiate a tumor from normal tissue
Detect the presence of a tumor based on measurements in the blood or secretions
such as ___ and ___, which are normally expressed during fetal development but do not occur normally in the tissues or sera of children and adults
oncofetal antigens
- AFP and CEA
proteins occurring in epithelial cellls that become elevated in tissue and serum in adeno- and squamous cell carcinomas, such as the ____, ___ and ___
CA 19-9, CA 125, and CA 15-3 proteins
β chain of human chorionic gonadotropin (β-hCG),
polypeptide hormones,
such as the placental isoform of alkaline phosphatase, that become elevated in the serum of patients with specific tumors
specific enzymes
None of the tumor markers discovered had sufficient specificity and sensitivity in the general population
It is not recommended for most tumor markers, especially in an asymptomatic population
Screening
The screening of primary hepatoma in Asian countries is based on the measurement of ___
Alpha-Fetoprotein (AFP)
serum AFP
First tumor marker recommended for screening for prostate cancer in men older than age of 50.
The purpose was to detect prostate cancer at early curable stages, when the tumor is still confined inside the organ.
Prostate-Specific Antigen (PSA) and Free PSA
Two major forms of Prostate-Specific Antigen (PSA) and Free PSA
Free PSA and a PSA –alpha1- antichymotrypsin (PSA-ACT)
Free PSA percentage of free PSA to PSA-ACT
Free PSA and a PSA –alpha1- antichymotrypsin (PSA-ACT)
Free PSA percentage of free PSA to PSA-ACT ratio may help differentiate _____ from __
benign prostate hyperplasia (BPH) from prostate cancer.
Several familial cancers are associated with germline mutations in various genes.
The most prominent are genes for susceptibility to ___ and ___ such as ___ and __ are now available to screen these families for the identification of carriers.
Susceptibility Genes
breast and ovarian cancer,
such as BRCA1 and BRCA2
One of the two most useful applications of tumor markers involves their use in monitoring the course during treatment of the cancer patient.
The measurement of serum tumor markers during treatment gives an indication of the effectiveness of the antitumor drug used and provides a guide for the selection of the most effective drug for each individual case.
Monitoring Treatment
Monitoring tumor markers for the detection of the recurrence following the surgical removal of the tumor.
It is desirable to monitor the patient using a ___ test to detect recurrence as early as possible.
It should be noted that the appearance of the most circulating tumor markers have a lead time of several months __ prior to the stage at which many of the physical procedures can be used for the detection of the cancer.
Detection of Recurrence
- highly sensitive tumor marke
- (3-6 months)
Determination is based on the assessment of tumor ____, which, in turn, determines how a patient should be treated.
- factors measured in the clinical laboratory also indicate risk and predict the length of a relapse-free, as well as overall, survival period at the time of the primary therapy.
High levels of serum tumor marker measured during diagnosis would indicate the presence of a ___ associated with a poor prognosis.
Prognosis
-aggressiveness
- malignant or metastatic tumor
Detecting the phenotypes in the blood circulation corresponding to early mutations of a cancer allows the detection of early neoplasm at the curable stage.
It should be noted that several risk factors may lead to ___, which can be identified and eliminated with diet adjustment and lifestyle change
Measurement of all mutant phenotypes and risk factors in the circulation would help to identify individuals at risk for cancer or detect early tumors in benign state.
malignant or metastatic tumor
-tumorigenesis
Previously, drugs used in chemotherapy were predominantly _____ that were considerably toxic and had limited efficacy.
Target Therapy
- DNA-active drugs
Inhibition of tumor cell proliferation may also be effective by introducing agents (or genes) that turn off the signaling pathway or pathways that specifically drive proliferation within a given tumor or tumor type.
Target Therapy
The prevailing new rationale is aimed at the development of ____ on the basis of characterized mechanisms of action.
The specific defect of the tumor identified by these new tumor markers should, therefore, lead to the design of more specific drugs, including antibodies and small molecules, which inhibit growth factor receptors tyrosine kinases.
Target Therapy
- target-selective “smart” drugs
Most used method to measure tumor markers
Immunoassays
- determined by analyzing specimens spanning the reportable range
Linearity
___ - antigen excess > analyte concentrations exceed the analytical range excessively
Hook Effect
circulating antibodies against human or animal immunoglobulin reagents > HAMAs
Heterophile antibodies -
Used to detect endocrine metabolites
Tumor markers – detect ____
Not subject to hook effect, lot-to-lot antibody variation and heterophile antibody
High Performance Liquid Chromatography
- catecholamine metabolites
identified in tissue sections typically from a fine-needle aspirate or biopsy samples
Immunohistochemistry and Immunofluorescence
___ incubated with tissue sections - detect the presence (or absence) of antigens using colorimetric or fluorescent secondary antibodies
Immunohistochemistry and Immunofluorescence
-Specific antibodies
-
Enzyme Assays
PSA - prostate cancer immunoassay
ALP alkaline phosphatase (ALP)
LDH Lactate dehydrogenase (LDH)
Biopsy indication
___ and ___
Screening
- AFP and PSA
high levels indicative of dse.
Diagnosis
- Metanephrines
- HVA/VMA
Prolactin
- PTH
- Chromogranin A
high levels asso w/ poor prognosis
receptor stat used for indication of chemotheraphy
Prognosis
- Beta2 microglobulin
- CA125
CEA
- LD
- Her-2/neu
ER
PR
Monitor efficacy of chemotheraphy: residual dse after surgery
Monitoring treatment
-CA125
CEA
CA19-9
AFP
hCG
- PSA
-SPE
Inc asso with relapse
CA15-3
CA125
CEA
AFP
hCG
PSA
Enzyme tumor markers
Prostate specific antigen
Lactate dehydrogenase
Alkaline phosphatase
Neuron specific enolase
Tumor marker: Prostate specific antigen
Tumor type Prostate cancer
Method Immunoassay
Specimen serum
Clinical utility Prostate cancer screening, therapy monitoring and recurrence.
TM: LDH
Tumor type Hematologic malignancies
Method Enzyme assay
Specimen serum
Clinical utility Prognostic indicator, elevated nonspecifically in numerous cancer
TM: ALP
Tumor type metastatic carcinoma of bone, hepatocellular carcinoma, osteosarcoma, lymphoma, leukemia
Method enzyme assay
Specimen serum
Clinical utility determination of liver yand bone involvement: nonspecific elevation in many bone- related and liver cancers
TM: Neuron- specific enolase
Tumor type Neuroendocrine tumors
Method radio immunoasssay, immunohistochemistry
Specimen serum
Clinical utility prognostic indicator and monitoring dse progression for neuroendocrine tumors
Serum protein tumor markers
Serum M proteins
serum free light chains
b2 microglobulin
Serum M proteins
Tumor type plasma cell dyscrasias
Method serum protein electrophoresis/immunofixation electrophoresis
Specimen serum
Clinical utility dx, therapeutic monitoring of plasma malignancies
serum free light chains
Tumor type plasma cell dyscrasias
Method immunoassay
Specimen serum
Clinical utility dx, therapeutic monitoring of plasma malignancies
b2 microglobulin
Tumor type hematologic malignancies
Method immunoassay
Specimen serum
Clinical utility prognostic marker for lymphoproliferative disorders
Endocrine tumor markers
ACTH adrenocorticotropic hormone
ADH antidiuretic hormone
C peptide
calcitonin
chromogranin a
cortisol
gastrin
GH growth hormoe
HVA homovalinic acid
5-HIAA hydroxyindoleacetic acid
Metanephrines (fractionated)
PTH
PRL
VMA
ACTH adrenocorticotropic hormone
Tumor type pituitary adenoma, ectopic ACTH-producing tumor
Method immunoassay
Specimen serum
Clinical utility prognostic marker for lymphoproliferative disordersx of ectopic- ACTH-producing tumor
ADH antidiuretic hormone
Tumor type posterior pituitary tumors
Method immunoassay
Specimen serum
Clinical utility DX of SIADH
C peptide
Tumor type insulin secreting tumors
Method immunoassay, elisa
Specimen serum
Clinical utility DX of insulinoma
calcitonin
Tumor type MTC and neuroendocrine tumors
Method immunoassay,
Specimen serum
Clinical utility screening response to therapy and monitoring recurrence of MTC
chromogranin a
Tumor type Pheochromocytoma, neuroblastoma, carcinoid tumor, cmall cell lung cancer
Method elisa ria
Specimen serum
Clinical utility aids in dx of carcinoid tumors phepchromocytomas and neuroblastomas
cortisol
Tumor type adrenal tumors
Method ia
Specimen serum/ urine
Clinical utility aids in dx of carcinoid tumors phepchromocytomas and neuroblastomas of cushing syndrome, adrenal adenoma
Gastrin
Tumor type neuroendocrine tumor
Method ia
Specimen serum
Clinical utility zollinger ellison syndrome gastrinoma
GH
Tumor type pituitary adenoma, ectopic GH-secreting tumors
Method ia
Specimen serum
Clinical utility dx and post monitoring of acromegaly
HVA homovalinic acid
Tumor neuroblastoma, pheochromocytoma, paraganglioma
Method hplc
Specimen 24hr urine
Clinical utility dx of carcinoid tumors
5-HIAA hydroxyindoleacetic acid
Tumor typecarcinoid tumors
Method hplc
Specimen 24hr urine
Clinical utility dx and screening of carcinoid tumors of pheochromocytoma
Metanephrines (fractionated)
Tumor type neuroblastoma, pheochromocytoma, paraganglioma
Method hplc
Specimen 24hr urine
Clinical utility dx and screening of pheochromocytoma
PTH
Tumor type parathyroid adenoma
Method ia
Specimen serum
Clinical utility dx and postsurgical monitoring of parathyroid adenoma
VMA
Tumor type neuroblastoma, pheochromocytoma, paraganglioma
Method hplc
Specimen 24hr urine
Clinical utility dx and screening of pheochromocytomaF neuroblastoma
nonseminomatous tumors
Germ cell tumor -
1. yolk sac tumor(endodermal sinus tumor)
AFP Increased
hCG No
2. cholirocarcinoma
AFP no
hCG inc
3. embronal carcinoma
AFP inc
hCG +/-
4. teratoma
AFP no
hCG No
Seminoma
GCT NONE
AFP Not elevated in pure tumors
hCG +/-
CHO and Cancer Ag tumor markers
CA19-9
CA15-3
CA27-29
CA-125
CA19-9
Tumor type Gastrointestinal cancer and adenocarcinoma
Method Immunoassay
Specimen Serum
Clinical utility Monitoring pancreatic cancer
CA15-3
Tumor type Metastatic breast cancer
Method Immunoassay
Specimen Serum
Clinical utility Response to therapy and detecting recurrence
CA27-29
Tumor type Metastatic breast carcinoma
Method Immunoassay
Specimen Serum
Clinical utility Response to therapy and detecting recurrence
CA-125
Tumor type ovarian cancer
Method Immunoassay
Specimen Serum
Clinical utility monitoring therapy
Receptor tumor markers
Estrogen receptor
progesterone receptor
Her-2/neu
Epidermal growth factor receptor
Estrogen receptor
progesterone receptor
Tumor type breast cancer
Method ihc
Specimen biopsy
Clinical utility hormonal therapy indicator
Her-2/neu
Tumor type breast cancer
Method ihc, fish, elisa
Specimen biopsy
Clinical utility prognostic and hormonal therapy indicator
Epidermal growth factor receptor
Tumor type head, neck, ovarian, cervical cancer
Method ihc
Specimen biopsy
Clinical utility prognostic indicator
Most well known angiogenic factors:
Vascular endothelial growth factor (VEGF)
Acidic and basic fibroblast growth factor (aFGF and bFGF)
Transforming growth factor alpha (TGF-alpha)
Most well known angiogenic factors:
Vascular endothelial growth factor (VEGF)
Acidic and basic fibroblast growth factor (aFGF and bFGF)
Transforming growth factor alpha (TGF-alpha)
