Transcript Telomerase and Cancer

Tumor Markers
Dr/ Ehsan Mohamed Rizk
A substance that is present in or produced by a
tumor or by the host in response to tumor’s
presence.
An ideal tumor marker: specific, sensitive, has
short half life, its concentration is correlated with
tumor burden and its assay is easy, reliable and
cost effective.
Clinical Application of Tumor Markers
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Screening - limited
Diagnosis - limited
Prognosis - limited
Tumor staging - limited
Tumor localization / radiotherapy - limited
Monitoring the effectiveness of therapy important
Detecting tumor recurrence or remission important
Telomeres
Without some form of correction the end replication
leads to the loss of 50-100 nucleotides from the newly
synthesized lagging strand at each chromosome end in
each round of duplication
In mammalian (and many other) cells, the solution to
this problem is that chromosome ends have a special
duplication machinery
= Telomerase
Telomerase (special type of reverse transcriptase) is a
protein-RNA complex that carry an RNA template for
synthesizing a repeated G-rich telomere.
Telomerase is unique in carrying its own RNA template
with it all the time.
Telomerase is composed of both RNA
and protein
How Telomerase extends the Telomere
Telomerase and Senescence
In most somatic tissues, telomerase is expressed at very
low levels or not at all -- as cells divide, telomeres shorten
Short telomeres may be a signal for cells to senesce (stop dividing)
Telomerase and Cancer
The presence of telomerase in cancer cells allows them
to maintain telomere length while they proliferate
Genetic Markers
Types of oncogenes
Type I oncogene:
• Spleen focusforming virus
(SFFV) is a
retrovirus that
induces
erythroleukemia
in mice
• SFFV encodes a
protein, gp55,
that activates
Epo receptors
on erythroid
precursor cells
Type II: HER-2/neu 0ncogene
RAS oncogene
Mutated N-ras gene is found in neuroblastoma and AML.
Mutated K-ras gene is found in pancreatic, colon, lung and bladder
cancers.
BCR/ABL oncogene
Tumor suppressor genes
1- p53
2- Retinoblastoma gene
BRCA1 and BRCA2
• BRCA 1 gene is located on ch 19 while BRCA 2
gerne is located on ch 13.
• Screening for familial breast-ovarian cancer
syndrome, and breast cancer in early-onset
breast cancer families
Oncofetal Antigens
Carcinoembryonic antigen:
• Described by Gold and Freedman in 1965 as a marker of
Colorectal Cancer.
• It also increases in pancreatic, gastric, lung, ovarian,
uterine and breast cancers.
• Molecular mass of approximately 200 kDa.
• Glycoprotein with carbohydrate composition ranging from
45 – 55 % encoded by a gene located on chromosome 19.
• CEA levels 5 – 10 times upper limit of normal suggests
cancer colon.
• CEA useful for staging and monitoring treatment but not
for screening.
Alpha fetoprotein
• Glycoprotein, found in fetal liver, yolk sac, GI tract,
biochemically related to albumin in adults
• half-life: 4~6 days
• Normal serum levels; At birth
30 ng/ml
>1 years old (adult) <10 ng/ml
• Increased
in
70%
HCC,
elevated
in
hepatoblastoma, 20~70% germ cell tumors (yolk
sac tumors, embryonal cell carcinoma) of testis
and ovary, except dysgerminoma
• The absolute AFP level correlates with tumor
bulk
• CSF to plasma ratio of AFP > 1:40 → suggest
CNS involvement.
• AFP-L3 %: > 10 % suggests presence of HCC.
• Increase in benign conditions that cause hepatic
parenchymal inflammation, hepatic necrosis and
hepatic regeneration, ex. hepatitis, pregnancy,
primary biliary cirrhosis, extrahepatic biliary
obstruction
Enzymes as tumor markers
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Alkaline phosphatase.
Lactate dehyrogenase (LDH).
Neurone specific enolase.
Prostatic acid phospatase.
Prostate specific antigen (PSA).
Urokinase plasminogen activator system.
Cathepsins.
Matrix metalloproteinase.
Hormones as tumor makers
Hormone
Type of cancer
ACTH
Small cell lung cancer – Cushing's syndrome
– Cancer colon- cancer prostate- cancer
ovary
Calcitonin
Medullary carcinoma of the thyroid
HCG
Chorio carcinoma – Testicular tumors
Human Placental
Lactogen
Trophoplastic tumors – gonads, lung and
breast cancers
ADH
Small cell lung cancer – tumors of adrenal
cortex, pancreas and duodenum.
Glucagon
Glucagonoma
Catecholamines
and its
metabolites
Pheochromocytoma
Seritonin and
5HIAA
Carcinoid tumors
Cytokeratins
Tissue
polypeptide
antigen (TPA)
Proliferation marker useful for monitoring
metastasis in breast , colon and ovarian
cancers
Differentiating choriocacinoma and HCC.
Tissue
polypeptide
specific antigen
(TPS)
Antigenic site on TPA complex.
Associated with proliferative activity of lung
tumors
Cytokeratin 19
fragments
(CYFRA)
Used for staging, monitoring treatment and
follow up of lung cancer
Squamous Cell
Carcinoma
Antigen (SCCA)
Elevated in a variety of squamous cell
carcinoma of cervix, lung, head and neck,
digestive tract, ovaries and urogenital tract
Used as a prognostic marker and detection of
recurrence.
Carbohydrate Markers (CA)
CA 15-3
monitor treatment and to detect recurrence in cancer breast
Normal: <31 U/ml
↑in 20% with localized breast cancer, ~80% with metastatic
disease, esp. if with bone involvment
Specificity of 86%, sensitivity of 30%
Also increased in gastric, pancreatic, cervical and lung
cancer
CA 27.29 High molecular glycoprotein - Increased in cancer breast
CA 549
CA 125
Cell surface glycoprotein, present during embryonic
development of coelomic epithelium and is present in adult
structures derived from it
Normal : <35 U/ml, t ½ : 4~5 days
For follow up of ovarian cancer, an increase may predict
recurrent disease, may precede clinical recurrence by
months. Correlate with tumor bulk
Blood group antigen- related cancer
markers
CA 19-9
•Elevated in patients with mucin-secreting
cancers (colorectal, pancreatic, ovarian
and gastric cancers)
•Diagnosis, monitor, detect relapse in
ovarian cancer, 70% specificity and 90%
sensitivity
•Mild ↑in pancreatitis
CA 242
A marker of pancreatic and colorectal cancers
CA 72-4
A marker for carcinoma of GIT and ovary.
Proteins as tumor markers
Β2 microglobulin
•Multiple myeloma – B -cell lymphoma - CLLWaldenstrom macroglobulinaemia
•Correlates with tumor burden, prognosis, response
to therapy. Increase with poor renal function
C-peptide
Insulinoma
Ferritin
Cancer liver, lung, breast and leukaemias
immunoglobulins
Multiple myeloma and B-cell lymphoma
Tyrosinase
Use RT-PCR to detect hematogenous spread of
melanoma cells from a solid tumor in peripheral
blood
S100B protein
↑in 70% with stage IV metastasized melanoma
Proteins as tumor markers
Melanoma associated
antigen
Melanoma
Pancreas- associated antigen Pancreas and stomach cancers
Pregnancy specific protein-1
Trophoblastic and germ cell tumors
Prothrombin precursor
Hepatocellular cacinoma
Thyroglobulin
Tumor-associated trypsin
inhibitor
Tissue-specific,
glycoprotein
produced by thyroid follicular cells
normal: <60 ug/L
Increased in cancer thyroid. Also
increased in breast and lung
cancers
Lung, Gastro intestinal and ovarial
tumors
Receptors as tumor markers
Estrogen
Receptors (ER)
2 isoforms: ER α + ER β
ERα → better prognosis, predictor of relapse in
cancer breast. Useful when deciding an adjuvant
hormone treatment
ERβ → distinct biological roles and ligand
binding specificity, good prognostic factor,
correlate with low grade and negative axillary LN
status
Progesterone
Receptors (PR)
Useful prognostic maker in cancer breast with ER
assay because PR synthesis is dependent on
estrogen action
Epidermal
growth factor
receptors
(EGFR)
Overexpression of EGFR has prognostic value in
many cancers: head and neck, ovarian, cervical
bladder and esophgeal cancers