NEWER TUMOR MARKERS
DR. BINA M. GADHIYA
DEPT OF BIOCHEMISTRY
TUMOR MARKER is a substance produced by a tumor or
by the host in response to a tumor which is used to
differentiate a tumor from normal tissue or to detect
the presence of a tumor based on measurements in
blood or secretions.
They are found in cells, tissues or body fluids.
Measured qualitatively or quantitatively by chemical
immunological or molecular biological methods.
They are biochemical or immunologic counterparts of
differentiation states of tumor.
Cancer a multigene disease (cluster of diseases)which
arises as a result of mutational & epigenetic changes
coupled with activation of complex signaling networks.
It involves alteration of three main classes of genes –
1)ProtoOncogenes 2)Tumor suppressor genes 3) DNA
This contribute to development of cancer genotype &
This alterations resist the natural & inherent death
mechanisms embedded in cells(apoptosis) coupled with
dysregulation of cell proliferation events.
These genetic alterations include gene rearrangements,
point mutations & gene amplifications leading to
disturbances in molecular pathways regulating cell
growth, survival & metastasis.
When these changes manifest in mazority of patients
with specific type of tumour this can be used as tumour
markers ( Biomarkers ) .
Can also be used for detection & developing targeted
therapies besides predicting responses to treatment.
This new tumor markers include a broad range of
biochemical entities such as:
1. nucleic acids
5. small metabolites
6. cytogenetic & cytokinetic parameters
7. whole tumor cells
8. cancer stem cells
Highly specific i.e. detectable in only one tumor,
not detectable in benign disease and healthy
Highly sensitive i.e. detectable when only a few
cancer cells are present
specific to a particular organ
Correlate with the tumour stage or tumour mass
correlate with the prognosis
have a reliable prediction value
But ideal tumour marker doesn’t exists
Ideal Tumour Marker should be….
In practice ,current tumour markers are useful for-
evaluating progression of disease status after initial
therapy & for monitoring subsequent treatment
PROSTATE SPECIFIC ANTIGEN :
Only marker used to screen for a common type of
cancer –prostate cancer.
PSA is a single chain glycoprotein specific for prostatic
Gene encoding PSA has been sequenced & located on
PSA is a serine protease of the kallikrein family.(KLK3).
Sandwich immunoassays are used to measure PSA.
UROKINASE PLASMINOGEN ACTIVATOR
Contains 1) UROKINASE PLASMINOGEN ACTIVATOR (uPA) A serine
2) uPA membrane bound receptor (uPAR)
3) uPA inhibitors ,PAI-1 & PAI-2
Cathepsins B & L activates uPA ,which interacts with its receptor
,uPAR & converts plasminogen to plasmin .
Plasmin degrades extracellular matrix (ECM) components & activates
MMPs which further degrade the ECM & activate & release growth
factors FGF & transforming growth factor –beta.
uPA IS the prognostic marker in breast cancer. ALSO in ovarian ,renal
cervical & other cancers.
It is measured by ELISA & commercially available kits for detection of
uPA & & PAI in tumor tissue.
Are lysosomal proteases.
Cathepsin B , D & L have role in tumor development & progression.
Expression & localization of CB & CD is altered in tumor tissue.
Increased expression is seen in –breast,gastric ,lung, prostate
cancer & melanomas.
Altered localization is seen in –colon ,thyroid cancers ,-gliomas
,breast epithelial tumors .
They are involved in tissue invasion through ECM degradation &
growth promotion by various growth factors –fibroblast growth
factor ,Insulin like growth factor-1,Epidermal growth factor .
Increased expression ECM proteases is seen in stromal cells at the
border between tumor cells & normal tissue .
Detection of CB & other growth factors in stromal cells & tumor
tissue may have prognostic value.CB is detected by ELISA.
RIA is used to detect cytoplasmic CD in tumor tissue. It can be
measured by western blot , immunohistochemistry & by activity.
MATRIX METALLO PROTEINASES
Zinc dependent endopeptidases capable of degrading components
Involved in tissue remodeling & wound repair
Also associated with tumor growth ,invasion & metastasis.
Increased expression of MMP-2 & MMP-9 is associated with
accelerated tumor progression in oral carcinoma ,lung
adenocarcinoma ,papillary thyroid carcinoma .
MMP-7 correlates with tumor aggressiveness in esophageal
Expression of MMP-1 is associated with lymph node metastasis in
cervical cancer & peritoneal metastasis in gastric cancer.
MMP inhibition may be therapeutic strategy for cancer.
MMPs are detected in tissue sections by immunohistochemistry
using specific antibodies & in tissue extracts & serum by
TUMOR ASSOCIATED TRYPSIN
Acute phase reactant & induced under strong
Increased in gastrointestinal & urologic cancers .
Useful marker for pancreatic cancer .
TATI in serum or urine is measured by
NUCLEAR MATRIX PROTEIN -22 : BLADDER CANCER
S-100 PROTEINS - MELANOMA
AUTOANTIBODIES TO TUMOR ANTIGENS
MARKERS OF ANGIOGENESIS : VASCULAR ENDOTHELIAL
GROWTH FACTOR (VEGF) , SOLUBLE Tie 2 RECEPTOR
corelate with development of metastasis.
THYROGLOBULIN : THYROID CANCER
CHROMOGRANINS : NEUROENDOCRINE TUMORS
HEAT SHOCK PROTEINS
BREAST, ENDOMETRIAL CANCER, OSTEOSARCOMA
Physiopathological features of tumor micro
environment (low glucose, oxygen) stimulate HSP
HSP 27 EXPRESSION is associated with poor prognosis in
gastric ,liver ,prostate carcinoma & osteosarcoma. Also
associated with poor response to chemotherapy in
HSP 70 is correlated with poor prognosis in breast,
endometrial, uterine ,cervical & bladder carcinoma.
Implication of HSP in tumor progression & response to
therapy has led to its successful targeting in therapy by
use of HSP in anticancer vaccines exploiting their ability
MMP 13 –MATRIX METALLOPROTEIN 13
POTENTIALLY NEW TUMOR MARKER FOR BREAST
Gene expression using microarray technology was
studied in breast cancer patients .MMP 13 WAS 100%
over expressed confirmed to be a secreted protein by
western blot analysis of the culture medium .
(HE4) HUMAN EPIDIDYMIS PROTEIN 4
Marker for ovarian cancer .
Gene for HE4 has been discovered using microarrays to
be overexpressed in epididymal tissue & later in ovarian
The algorithm termed RISK OF MALIGNANCY INDEX
(ROMI) incorporating HE4 & CA 125 was accurate in
classifying a high percentage of women with epithelial
It is measured by enzyme immunoassay .
Ova1 1ST IVDMIA PROTEOMIC
DIAGNOSTIC FOR OVARIAN CANCER.
Qualitative serum test that conbines results of 5 immunoassays into a
single numeric score.
5 markers are –CA 125, PREALBUMIN , Apo A1 , Transferrin & Beta 2
Indicated in women who over age 18 & present with adnexal mass for
which surgery is planned & yet not referred to oncologist .
OVA1 score is calculated using OvaCalc software.
Expected value for probability of malignancy -
in premenopausal women-1)HIGH –OVA 1≥ 5.0 2) LOW OVA1 < 5.0
In postmenopausal women -1)HIGH –OVA 1≥ 4.4 2) LOW OVA1 < 4.4
BLOOD GROUP ANTIGEN RELATED
CA 72-4 : NEWER TEST FOR OVARIAN, PANCREATIC &
STOMACH CANCER . Studies of this marker are still in
CA 19-9 : PANCREATIC, GASTROINTESTINAL, HEPATIC
.best for pancreatic cancer.
CA 19-5 : PANCREATIC, GASTROINTESTINAL , OVARIAN
CA 50 : PANCREATIC, GASTROINTESTINAL, COLON
CA 242 : PANCREATIC, GASTROINTESTINAL
RECEPTORS & OTHER TUMOR MARKERS
ESTROGEN & PROGESTERONE RECEPTORS : INDICATORS
OF HORMONAL THERAPY IN BREAST CANCER.
ANDROGEN RECEPTORS : PROSTATE CANCER.
HEPATOCYTE GROWTH FACTOR RECEPTOR (c-MET) :
COLORECTAL , HEPATOCELLULAR, BREAST, PROSTATE,
EPIDERMAL GROWTH FACTOR RECEPTORS : OVER
EXPRESSION HAS STRONG PROGNOSTIC VALUE.
CATECHOLAMINE METABOLITES - VMA, HVA
,METANEPHRINES :NEUROBLASTOMA ,
HYDROXYPROLINE : BONE METASTASIS ( BREAST ),
LIPID ASSOCIATED SAILIC ACID : GASTROINTESTINAL
LYSOPHOSPHATIDIC ACID : A POTENTIAL BIOMARKER FOR
OVARIAN & OTHER GYNEACOLOGICAL CANCERS.
Deviations from diploid chromosome to hypo & hyper-
diploidy as well as aneuploidy are noted in malignant
Sister chromatid exchanges & translocations give rise to
structural aberrations are scored using various banding
techniques. Philadelphia chromosome is associated with
CML due to translocation between chromosomes 9 &
Double minutes & homogenously stained regions
indicative of gene amplifications are often observed in
malignant cells that can serve as markers.
Somatic mutations are promising biomarkers for cancer
risk as they can capture genetic events associated with
Enhanced cell proliferation ,most important hallmark of
cancer can be assessed by flow cytometric analysis of
DNA Content ,which is automated, objective & rapid
allowing large number of cells to be measured.
Identification of S phase cells & analysis of number of
antigenic determinants of proliferation (PCNA, Ki67,
NOR, etc ) are studied by molecular cell biology
techniques which can be used as complementary
Proteins encoded by mini chromosome maintenance
genes (MCM) are also proposed as useful markers of
proliferation ; with high levels of gene expression
indicating poor prognosis.
Gene deletions can be discovered by PCR using
microsatellite probes to various chromosomes & sites .
Random chromosomal abnormalities are associated with
Mutations & loss of heterozygosity within several proto-
oncogenes can lead to microsatellite instability .
Detection of this MSI in pathological tissue samples &
comparison with normal tissue represents a valuable
tool for early detection , at pre neoplastic stage.
Establishment of biomarkers require a comprehensive
understanding of molecular mechanisms & cellular
processes underlying the initiation of cancer, especially
focusing on how small changes in only a few regulatory
genes or proteins can disrupt a variety of cellular
In the post genomic era , with the availability of
complete human genome sequence & recent
technological advancement such as high throughput
DNA sequencing , microarrays & mass spectrometry, the
plethora of potentially informative cancer biomarkers
has expanded dramatically.
Oncogenes are derived from proto-oncogenes that may
be activated by dominant mutations ,insertions ,
deletions, translocations , or inversions.
Most oncogenes code for proteins needed for
proliferation , & their activation leads to cell division.
Most oncogenes are associated with hematologic
malignancies ,such as leukemia & to a lesser extent
solid tumors .
More than 40 proto oncogenes are recognized but only
few are useful as tumor markers.
PROTEINS Coded by ras genes are located in inner face of cellular
They bind to GDP/GTP & function as molecular switches that regulate
mitogenic signals from growth factor to nucleus by signal transduction
This are activated in association with protein tyrosine kinase receptors
Mutated N RAS is critical step in carcinogenesis & is found in
Neuroblastoma & Acute myeloid leukemia
Single point mutation in K RAS AT 12th position leads to change of amino
acid from glycine to valine in p21 protein & is most frequently found in
cancer & correlates with poor prognosis .
Mutations of ras oncogenes have been detected in DNA in stool of
symptomatic & asymptomatic patients of colorectal cancer, suggesting a
novel ,noninvasive paradigm for population screening.
ASCO in 2009 has formalized that diagnosis of metastatic colorectal cancer
with wild type KRAS tumors are likely to benefit from monoclonal antibody
treatments targeting the EGFR pathways such as CETUXIMAB &
C- myc gene
Binds to DNA & is involved in transcription regulation.
Gene product p62 is located in nucleus of transformed
Translocation results in activation of this gene & is
associated with poor prognosis. Increased expression is
seen in T & B cell lymphoma ,sarcoma .
Over expression of p62 is also seen in70 to 100% of
primary breast cancers & can be detected with
This gene codes for EGF family of tyrosine kinase
receptors which are involved in cell proliferation ,
differentiation & survival.
Amplification of this gene is found in Breast, Ovarian &
HERCEPTIN treatment is administered only to those
breast cancer patients who have Her-2/neu
Immunohistochemistry is used to detect increased
expression of this protein.
FISH is used for detection of HER-2/neu gene
BCL-2 oncogene codes for a protein which inhibits
apoptosis, especially lymphoma & leukemia cells.
Activation of this BCL-2 gene is due to 14:18
translocation resulting in formation of BCL-2 protein.
Overexpression of BCL-2 gene is associated with
development of resistance to cytotoxic cancer
BCR-ABL FUSION GENE
A balanced translocation between chromosomes 9 & 22
creating BCR- ABL fusion gene ( Philadelphia
chromosome )seen in 90% of CML patients.
Protein derived from this fusion is active tyrosine
kinase that activates several signaling pathways, leading
to uncontrolled growth , inhibition of apoptosis &
Detection of BCR-ABL gene by RT-PCR is useful in
diagnosing CML & monitoring residual disease in
patients who have undergone bone marrow
Several strategies target the BCR-ABL gene by
oligonucleotides or the BCR-ABL kinase domain by
tyrosine kinase inhibitor ST1571 (GLEEVEC OR IMATINIB
Tumor suppressor genes
This genes are isolated from many solid tumors .
The oncogenicity of tumor suppressor genes is derived from loss
of genes . Deletion or monosomy leads to loss of tumor
P53 Gene activates molecular processes that delay the cell cycle
progression of proliferating cells & stimulate DNA repair process.
Mutant p53 gene is useful biomarker for predicting prognosis &
patients response to therapy.
Gene replacement therapies targeting p53 aims at restoration of
p53 function in cancer cells by introduction of exogenous p53.
APC gene is deactivated in many tumors (oesaphageal
adenocarcinoma & squamous cell carcinoma.) hypermethylated
APC gene in the blood is associated with poor survival.
Mutations in BRCA 1 & BRCA 2 gene have an inherited
predisposition to develop breast & ovarian cancer.
In colon cancer ,deletion or reduced expression of DCC
gene correlates with increasing stage & poor prognosis.
PTEN mutation or loss of expression is associated with
more advanced stage & is a poor prognostic indicator in
various cancers, including breast, cervical,
hepatocellular & endometrial.
Epigenetic modifications occur directly through DNA
methylation of genes or indirectly by methylation
,acetylation or phosphorylation of histones & other
proteins around which DNA is wound to form chromatin.
Activity of DNA methyl transferases are altered in tumor
cells & are associated with developmental
Genomic hypo methylation leads to genomic instability
& stronger gene expression .
Local promoter CpG island hypermethylation induces
functional silencing of tumor suppressor genes.
Hypermethylation of p16 promoter in the circulating
serum DNA correlate well with recurrent colorectal
Aberrant methylation of p16Ink4 & MGMT promoters
can be detected in DNA from the sputum of patients
with squamous cell carcinoma nearly 3 years before
Alterations in methylation patterns of group of genes in
sputum samples may be an effective & non invasive
approach for identifying smokers at risk of developing
The development of therapeutics that reverse
epigenetic alterations in cancer cells along with
prognostic & diagnostic assays on gene methylation
patterns are promising new avenues for future
improvements in patient care.
Cells as Biomarkers
Circulating Tumor Cells [CTCs] :
They provide early and reliable indication of disease
progression and survival of patients on systemic therapy
for metastatic breast cancer as early as 3-4 weeks after
initiation of therapy.
Superior to standard tumor markers in predicting
Can be used as an early predictor of treatment efficacy
and extremely in sparing patients from futile therapy.
Can be detected by immunocytometry.
T-regulatory cells [CD4+,CD25+,Foxp3] :
These are important in inducing and maintaining
peripheral self-tolerance and thus preventing immune
Increased T regulatory activity is associated with poor
response to tumor antigens and contribute to immune
dysfunction resulting in tumor growth.
T-regulatory cells may serve as surrogate immune
marker of cancer progression and perhaps prognosis.
It is also useful as a predictor of response to therapies.
CD 90 IS A DIAGNOSTIC MARKER TO DIFFERENTIATE
BETWEEN MALIGNANT PLEURAL MESOTHELIOMA & LUNG
CARCINOMA WITH IMMUNO HISTOCHEMISTRY .
Cancer Stem Cells [CSC] :
Subpopulation of cancer cells which resemble the
developmental hierarchy of the normal tissue from which
the tumor arose.
Evidence for existence of CSC initially came from studies of
CSC are now demonstrated in many solid tumors including
glioblastoma, medulloblastoma, breast cancer, melanoma
and prostate cancer.
CSC are resistant to chemotherapy and radiation therapy.
Eradication is the critical determinant in achieving cure.
Identifying and characterizing CSC for every possible tumor
is of paramount importance and will likely lead to new
Hepatocellular cancer –
HBV promotes carcinogenesis through genetic instability
generated by its common integration in host DNA .
These markers include :
1. Analysis of viral DNA or proteins or antibodies produced
against the viral proteins.
Cervical Cancer :
Persistent infection of high-risk type of human papilloma
HPV-viral load in biopsy specimen.
Antibodies against HPV-E6 and E7 serves as markers of an
invasive HPV associated malignancy.
2 new HPV Vaccines “Gardasil” and “Cervarix” are highly
immunogenic and effective in preventing infections with high
risk-HPV types 16 & 18.
EBV has been directly implicated in pathogenesis of Burkitt’s
lymphoma, NHL, nasopharyngeal carcinoma.
Detection of quantification of plasma EBV-DNA serves as a
useful molecular marker for diagnosis monitoring and
prediction of relapse in patients with nasopharyngeal
carcinoma and Hodgkin’s lymphoma.
(PCA 3) PROSTATE CANCER ANTIGEN 3
It is a new gene based test carried out on urine sample .
PCA 3 is highly specific to prostate cancer & not
increased in benign enlargement or inflammation of
This testing holds potential in men with elevated PSA
levels but no cancer on initial biopsy.
PCA 3 urine test will decide whether a new biopsy is
Mutations in mitochondrial DNA particularly in D-loop
region have found in many cancers .
Mutated mt DNA has been detected in body fluids of
cancer patients & is much more abundant than mutated
nuclear p53 DNA.
Bio-energetic index of cell has been suggested for
classification and prognosis of cancer, besides
predicting the response to therapy.
Positron emission tomography allows non invasive and
quantitative analysis of various biologic process.
It uses a glucose analogue [2-deoxy-D-glucose] labelled
with positron emitter Fluorine 18.
FDG that is partially metabolized and trapped as its
phosphate [2-DG-6-P] in the tumor tissue, thus,
localizing the tumor
Extent of increase in glucose utilization measured by
FDG-PET has been co-related with degree of malignancy
in some tumors.
Glycolytic inhibitors like 2-deoxy-D-glucose are
selectively cytotoxic to tumor cells sensitizing it to
ionizing radiations. 2-DG has the potential to enhance
the efficacy of chemotherapy.
Clinical trials in patients with malignant brain tumors
using a hypo fraction radio-therapy protocol combined
with 2DG have been very encouraging.
Studying cancer through metabolomics could reveal
new biomarkers for cancer that could be useful for its
future prognosis ,diagnosis & therapy.
Targeted therapies display greater selectivity for tumor cells.
Eg : Small molecule drugs that inhibit the activity of tyrosine
kinases [ Eg : Imatinib and Erlotinib targeting ABL & EGFR].
Antibody bevacizumab targets a growth factor that stimulates
tumor blood vessel growth.
One of the best markers for human cancer associated with
only malignant tumors.
Telomerase enzyme ensures the maintenance of telomere and
thereby protecting the cell from degradation and cell death.
In cancer cells telomerase shuttling system is impaired.
The TRAP (telomeric repeat amplification protocol) assay is
used for detection of telomerase activity.
It has been a target for anti-cancer therapeutics that turn off
telomerase and there by inhibit tumor growth.
Currently two clinical trials : one using a vaccine [GRNVAC1]
and the other a lapidated drug [GRN163L] are under way to
evaluate the efficacy of telomerase inhibitors.
Histone deacetylases [HDACs]
HDACs are associated with oncogenesis by regulating the
expression of certain tumor suppressor genes leading to
excessive proliferation and tumorogenesis.
They have recently been the attractive targets for cancer
HDAC inhibitors are currently under clinical investigation
in a number of hematological malignancies and solid
Mammalian target of rapamycin
Evolutionarily conserved serine threonine protein kinase that
belongs to PIKK (phosphoinositide 3 kinase (PI3K) –related kinase
) family .
Plays an important role regulating cell growth & proliferation .
Upon activation mTOR increases phosphorylation levels of its
downstreams targets that include P70S6K & 4EBP1, which leads
to increased levels of translation , ribosome biogenesis &
reorganization of actin cytoskeleton & inhibition of autophagy .
A no. of m TOR inhibitors have potent anti-proliferative
properties which make them useful for cancer chemotherapy
particularly of advanced solid tumors showing higher levels of
expressions of phosphorylated S6.
Peptidyl-Prolyl-Isomerase [PPIase], PIN1 regulates post
phosphorylation event which is in the form Cis and Trans
isomerization of phosphoserine/threonine – proline peptide
bonds at selective sides.
Over expression of PIN1 has been reported in human breast
cancer cell lines and tissues, and its expression closely
correlates with the level of cyclin D1 in tumors.
PIN1 opens a new target for the development of specific
therapeutics as phosphorylated p53 is known substrates of
Inhibition of PIN1 induces mitotic arrest and apoptosis in
tumor cell lines
Recent studies with PIN1 inhibitor Juglone delays the growth
of various tumor cell lines.
Proteomics analysis of saliva
Non invasive method for identifying biomarkers for human
4 proteins in saliva have been found to be useful markers of oral
cancers with 90% sensitivity & 83% specificity for oral squamous
cell carcinoma .
Calcium binding protein MRP 14
CD 59 –overexpressed on tumor cells that enables them to
escape from complement dependent & antibody mediated
Profilin 1 a protein involved in several signaling pathways
,secreted in tumor microenvironments during the early
progressive stage of tumorogenesis.
Catalase, a member of antioxidative system is involved in
carcinogenesis & tumor progression .
ADIPONECTIN & LEPTIN – IN BREAST
Adiponectin & leptin are involved.
Studies show that leptin m RNA expression is higher than
adiponectin m RNA expression in cancer cells.
Adiponectin inhibits proliferation of cancer cells. Leptin
stimulates growth of cancer cells.
Adiponectin inhibits leptin induced cell proliferation.
ADHESION MOLECULES & METASTASIS
Cell adhesion molecules, including Integrins, Selectins &
Cadherins regulate many steps of metastatic process.
Increased serum levels of E selectin, Inter cellular adhesion
molecule (ICAM) & Vascular adhesion molecule (VCAM)
indicate late stage of Breast cancer or the occurrence of
metastasis & hence a poor prognosis.
Stress & cancer
Under normal circumstances trigerring ATF 3 gene in
stressfull conditions protects the body from harm by causing
normal cells to commit suicide .
Cancer cells are able to switch on ATF 3 GENE in immune
cells & causes malfunction of immune cells & allows cancer
cells to escape from the tumor & spread to other parts of
MICROARRAY BASED MARKERS
Amplichip p450 – Roche diagnostics
Oncotype Dx - Genomic health inc.
Mammaprint - Agendia inc.
Tissue of origin test – Pathwork diagnostics .
Bioplat-a software for human cancer biomarker discovery
Micro array based analytes will revolutionize the future of
cancer therapy by providing biomarkers on their genetic
THE PRECLINICAL STRATEGY OF CANCER BIOMARKER
DISCOVERY ARE SENSITIVE & SPECIFIC ENOUGH
-FOR EARLY CANCER DETECTION
-FOR MONITORING DISEASE PROGRESSION &
-FOR PROPER TREATMENT SELECTION,
PAVING THE WAY TO INDIVIDUALIZED CANCER TREATMENT.
NEW ERA IN CLINICAL ONCOLOGY WILL BE GUIDED BY
MOLECULAR ATTRIBUTES OF INDIVIDUAL PATIENTS THAT WILL
ALSO ANSWER ABOUT BIOLOGIC BEHAVIOR OF TUMORS .
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MMP13 is potentially a new tumor marker for breast cancer diagnostic.
[PubMed – indexed for MEDLINE]
BioPlat- a software for human cancer biomarker discovery.[Bioinformatics.
Involvement of adiponectin and leptin in breast cancer: clinical and in vitro
studies.[ENDOCR RELAT CANCER, 2009 December;16(4): 1197-210]
Detecting cancer through markers (Dr. Mohini Bhargava- Express Healthcare)
Cancer biomarker discovery : current status & future perspectives.
( International journal of Radiation Biology ).
Stress fuels cancer spread by triggering master gene :ATF 3.