Tumor markers are biological substances that are produced by cancer cells or the body's response to cancer. Ideal tumor markers should be highly specific, sensitive, correlate with tumor stage/mass, and predict prognosis. Recent advances include new genetic and viral biomarkers. Tumor markers can be classified as hormones, oncofetal antigens, enzymes, tumor-associated proteins, receptors, and genetic markers. Oncogenes like RAS and C-myc can also serve as markers when mutated or translocated. Establishing biomarkers requires understanding how small molecular changes disrupt cellular functions and cancer initiation.

1. TUMOR MARKERS WITH RECENT
ADVANCES
DR. PRINCE LOKWANI
DEPT OF PATHOLOGY
SAIMS INDORE
GUIDED BY: DR.AMIT V. VARMA

2. What are Tumor Markers ？
Biological substances synthesized and released by
cancer cells themselves or
Produced by the host in response to the presence of
tumor
Most tumor markers are proteins
Detected in a solid tumor, in circulating tumor cells
in peripheral blood, in serum, lymph nodes, in bone
marrow, or in other body fluids .

3. Clinical applications of Tumour markers
In practice ,current tumour markers are useful for
evaluating progression of disease status after initial
therapy & for monitoring subsequent treatment
modalities.

4.  Highly specific i.e. detectable in only one tumour , not detectable in
benign disease and healthy subjects
 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….

5. 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)Proto-oncogenes 2)Tumor
suppressor genes 3) DNA repair genes.
This contribute to development of cancer genotype & phenotype.
This alterations resist the natural & inherent death mechanisms embedded in
cells(apoptosis) coupled with dysregulation of cell proliferation events.
Cancer

6. 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 majority 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.

9. Classification of Tumour markers
HormonesOncofetal AntigensEnzymesTumor-Associated ProteinsReceptorsGenetic

15. HORMONES AS TUMOR MARKERS
ACTH :Cushing’s Syndrome ,lung Cancer
ADH :Lung , Adrenal Cortex , pancreatic
Bombesin :Lung
Calcitonin :Medullary Ca Thyroid
VIP : Pheochromocytoma, Neuroblastoma
HCG :Choriocarcinoma, Embryonal

16. ENZYMES AS TUMOR MARKERS
Prostatic Acid Phosphatase : Prostate
Alcohol Dehyrdrogenase & Aldolase : Liver Cancer
Alkaline Phosphatase : Bone, Liver, Leukemia
Neuron Specific Enolase : Small Cell Lung Cancer, Neuroblastoma,
Melanoma
Lactate Dehydrogenase : Lymphoma , Leukemia

17. ONCOFETAL ANTIGENS
AFP : Hepatocellular ,Germ Cell Tumor,
 Carcino-fetal ferritin : Liver
CEA : Colorectal, Gastrointestinal, Lung, Breast ,Pancreatic
Squamous Cell Antigen : Cervical, Lung, Skin, Head & Neck
Tennessee Antigen : Colon, Gastrointestinal, Bladder
Cytokeratins :
1)Tissue Polypeptide Antigen : Breast, Colorectal, Ovarian, Bladder
2)Tissue Polypeptide Specific Antigen
3) Cytokeratin 19 Fragments (Cyfra-21-1) -A Prognostic marker for Non Small Cell Lung Cancer.

18. Proteins as tumor markers
Beta2-macroglobulin : Multiple Myeloma, CML, Waldenstrom’s
macroglobulinemia
C-peptide : Insulinoma
Ferritin : Liver, Lung, Breast, Leukemia
Immunoglobulins : Multiple Myeloma, Lymphomas
Melanoma Associated Antigen : Melanoma
Des-gamma-carboxy prothrombin : Hepatocellular Carcinoma
Soluble Mesothelin Related Peptides : Mesothelioma, Ovarian

19. 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 correlate with development of metastasis.
Thyroglobulin : Thyroid Cancer
Chromogranins : Neuroendocrine tumors

20. CARBOHYDRATE MARKERS or MUCIN TUMOR
MARKERS
Ca-125 : Ovarian, Endometrial
Ca-15-3 : Breast, Ovarian
Ca-549 : Breast, Ovarian
Ca-27.29 : Breast
Mucin-like carcinoma associated antigen (MCA) : Breast , Ovarian
Du-pan-2 : Pancreatic

21. BLOOD GROUP ANTIGEN RELATED MARKERS
Ca 72-4 : Newer test for Ovarian, Pancreatic & Stomach Cancer (Studies of this marker are still
in progress)
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

22. 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, Cervical Cancer.
Epidermal Growth Factor Receptors : Over expression has strong prognostic value.

23. Catecholamine Metabolites - VMA, HVA ,Metanephrines :Neuroblastoma ,
Pheochromocytoma
Hydroxyproline : Bone Metastasis ( Breast ), Multiple Myeloma
Lipid Associated Sailic Acid : Gastrointestinal ,Lung ,Rheumatoid
Polyamines
Lysophosphatidic Acid : A Potential biomarker for Ovarian & other
Gyneacological Cancers.

24. Viral Biomarkers
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.
2.HBsAG
3.HBeAG
4.anti-HBV core-antigen.
5.anti-HBeAG, anti-HbsAG.

25. Cervical Cancer :
Persistent infection of high-risk type of human papilloma virus.
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.

26. Genetic markers
Deviations from diploid chromosome to Hypo & Hyper-diploidy as well as Aneuploidy
are noted in malignant tumors.
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 & 22.
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 malignant transformations.

27. 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 markers.
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.

28. Gene deletions can be discovered by PCR using microsatellite probes to various
chromosomes & sites .
Random chromosomal abnormalities are associated with clinical cancer.
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.

29. 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 functions.
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.

30. Oncogenes
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.

31. RAS GENES
Proteins coded by RAS genes are located in inner face of cellular membranes.
They bind to GDP/GTP & function as molecular switches that regulate mitogenic
signals from growth factor to nucleus by signal transduction pathways .
These are activated in association with protein tyrosine kinase receptors
Mutated N RAS is critical step in carcinogenesis & is found in Neuroblastoma &
Acute myeloid leukemia

32. 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 pattern for population screening.
ASCO in 2009 has formalized that diagnosis of metastatic colorectal cancer
with wild type K RAS tumors are likely to benefit from monoclonal
antibody treatments targeting the EGFR pathways such as CETUXIMAB &
PANITUMUMAB.

33. C- myc gene
 Binds to DNA & is involved in transcription regulation.
Gene product p62 is located in nucleus of transformed cells.
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 in 70 to 100% of primary breast cancers & can be detected
with immunohistochemistry.

34. Her-2/neu (ERBB2)
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 & gastrointestinal tumors.
HERCEPTIN treatment is administered only to those breast cancer patients who have
Her-2/neu amplification.
Immunohistochemistry is used to detect increased expression of this protein.
FISH is used for detection of HER-2/neu gene amplification.

35. BCL-2 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 chemotherapy .

36. 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 & neoplastic
transformation.
Detection of BCR-ABL gene by RT-PCR is useful in diagnosing CML & monitoring residual
disease in patients who have undergone bone marrow transplantation.
Several strategies target the BCR-ABL gene by oligonucleotides or the BCR-ABL kinase
domain by tyrosine kinase inhibitor ST1571 (GLEEVEC OR IMATINIB MESYLATE )

37. Tumor suppressor genes
These 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 suppressor genes
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.

38. 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.

40. New tumor markers include a broad range of biochemical entities such as:
1. nucleic acids
2. proteins
3. sugars
4. lipids
5. small metabolites
6. cytogenetic & cytokinetic parameters
7. whole tumor cells
8. cancer stem cells

41. ISOCITRATE DEHYDROGENASE 1
IDH1 can be used as a plasma biomarker for the diagnosis of NSCLCs,
particularly lung adenocarcinoma, with relatively high sensitivity and
specificity.

42. UROKINASE PLASMINOGEN ACTIVATOR SYSTEM
Contains 1) UROKINASE PLASMINOGEN ACTIVATOR (uPA) A serine protease
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 .
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.

43. CATHEPSINS
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 of 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.

44. MATRIX METALLO PROTEINASES
Zinc dependent endopeptidases capable of degrading components of ECM.
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 carcinoma.
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 immunoassay.

45. HEAT SHOCK PROTEINS
Physiopathological features of tumor micro environment (low glucose, oxygen)
stimulate HSP induction.
HSP 27 Expression is associated with poor prognosis in gastric ,liver ,prostate
carcinoma & osteosarcoma. Also associated with poor response to chemotherapy
in leukemia patients.
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 to act as immunological adjuvant.

46. MMP 13 –MATRIX METALLOPROTEIN 13
Potentially new tumor marker for breast diagnosis.
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 .

47. (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 cancer tissue.
The algorithm termed RISK OF MALIGNANCY INDEX (ROMI) incorporating
HE4 & CA 125 was accurate in classifying a high percentage of women with
epithelial ovarian cancer.
It is measured by enzyme immunoassay .

48. TUMOR ASSOCIATED TRYPSIN INHIBITOR(TATI)
Acute phase reactant & induced under strong inflammatory conditions
Increased in gastrointestinal & urologic cancers .
Useful marker for pancreatic cancer .
TATI in serum or urine is measured by radioimmunoassay.

49. Ova1 1ST IVDMIA PROTEOMIC DIAGNOSTIC FOR OVARIAN
CANCER.
Qualitative serum test that combines results of 5 immunoassays into a single numeric score.
5 markers are –CA 125, PREALBUMIN , Apo A1 , Transferrin & Beta 2 macroglobulin
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

50. Epigenetic markers
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 abnormalities.
Genomic hypo methylation leads to genomic instability & stronger gene
expression .
Local promoter( CpG )hypermethylation induces functional silencing of tumor
suppressor genes.
Hypermethylation of p16 promoter in the circulating serum DNA correlate well
with recurrent colorectal cancer.

51. Aberrant methylation of p16Ink4 & MGMT promoters can be detected in DNA
from the sputum of patients with squamous cell carcinoma nearly 3 years
before clinical diagnosis.
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 lung cancer.
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.

52. 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 prognosis.
Can be used as an early predictor of treatment efficacy and extremely in sparing
patients from futile therapy.
Can be detected by immunocytometry.

53. T-regulatory cells [CD4+,CD25+,Foxp3] :
These are important in inducing and maintaining peripheral self-tolerance and thus
preventing Immune pathologies.
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 .

54. Cancer Stem Cells [CSC] :
Subpopulation of cancer cells which resemble the developmental hierarchy of the
normal tissue from which the tumor arise.
Evidence for existence of CSC initially came from studies of AML.
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 therapeutic avenues.

55. (PCA 3) PROSTATE CANCER ANTIGEN 3 GENE
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 prostate.
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 needed.

56. Mitochondrial Markers
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.

57. Metabolic Biomarkers
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

58. 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.

59. Therapeutic Biomarkers
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.

60. Telomerase
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.

61. 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 therapeutics.
HDAC inhibitors are currently under clinical investigation in a number of
hematological malignancies and solid tumors.

62. 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 mTOR 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.

63. PIN1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 PIN1.
Inhibition of PIN1 induces mitotic arrest and apoptosis in tumor cell lines
Recent studies with PIN1 inhibit or delays the growth of various tumor cell lines.

64. Proteomics analysis of saliva
Non invasive method for identifying biomarkers for human cancers
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 immune responses.
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 .

65. ADIPONECTIN & LEPTIN – IN BREAST CANCER
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.

66. 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.

67. 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 the body.

68. 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 makeup.

69. 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 .

70. PARANEOPLASTIC SYNDROME
Paraneoplastic syndrome is a disease or a symptom that is a consequence
of cancer, but not due to the presence of local cancer cells.
Paraneoplastic syndrome is mediated through:
Cross reacting antibodies
Production of physiologically active factors
Interference with normal metabolic pathways
idiopathic

71. PARANEOPLASTIC SYNDROME
Paraneoplastic syndrome is a disease or a symptom that is a
consequence of cancer, but not due to the presence of local cancer
cells.
All neurological abnormalities Not Caused By:
Invasion by the tumor or its metastases
Infections
Ischemia, metabolic or nutritional deficits
Surgery or other treatment modalities
“Remote effects of cancer on the nervous system”

72. Paraneoplastic Syndromes May Affect Any Portion of the
Nervous System
Cerebral cortex
Brainstem
Spinal cord
Peripheral nerves
Neuromuscular junction
Muscle

73. Autoimmunity

74. Paraneoplastic syndrome
Classification
Endocrine: hormone secreting tumours
Neurological: immune mediated
Mucocutaneous
Haematological
others
Overview of:
Syndromes
Causes
Therapy

76. Thank You