Lecture notes on New definition and new theory (stem cell-microRNA Theory) of cancer General concept of cancer By Dr.Rkdhaugoda CTGU, YICHANG CHINA- Visiting Assistant professor ( FROM NEPAL) 2014- MAY-5th

1. Lecture notes on New definition and
new theory (stem cell-microRNA
Theory) of cancer
General concept of cancer
By Dr.Rkdhaugoda
CTGU, YICHANG CHINA-
Visiting Assistant professor ( FROM NEPAL)
2014- MAY-5th

2. CANCER AT A GLANCE- CURRENT
CONCEPT
 big challenging SUBJECT even though our advance medical knowledge
 few oncologic diseases we can able to treat when detected in early stage by
means surgery, chemotherapy and radiotherapy
 ACTUAL CAUSE IS NOT KNOWN
 MULTI-FACTORIAL CAUSES- PROPOSED
 PROPOSED MECHANISM – MUTATION OF NORMAL GENE-FORMING
ONCOGENE- UNCONTROLLED CELL GROWTH, METABOLIC CHANGES
INCREASED GLYCOLYSIS.
 New theory- stem cell theory-deregulated microRNA
 DIAGNOSTIC AND MANAGEMENT PROBLEM. due to late detection, and
multiple metastases locally as well as distantly
 no specific ways to prevent, as it is multifactorial, acquired and genetic
dependent causes.
 High mortality/ morbidity- high cost/ expensive.

3. CANCER AT A GLANCE
• There are many cause have been listed for the
causation or initiation of oncologic diseases
• genetic causes- mutation
• There are over 200 different known cancers that
affect humans
• environmental factors like smoking, various
viruses, foreign proteins, chemicals, toxins,
radiations, immune deficiency conditions like
AIDS, anti cancer drugs and many other stress
factors.

4. Normal cell physiology
• Controlled cell growth – normal cell replication
• Controlled cell transformation- normal stem cell
• Normal DNA- repair mechanism
• Destruction of unrepaired/ abnormal-cell-naturally-
apoptosis
• Limited life span- cancer cells live for longer time.
• Normal level of –IkBa AND NFkB; TNF-alpha,IKK
• Normal level of intracellular Ca:Mg ( 1:4 )
• NORMAL- CELL METABOLISM-normal glycolysis
• NORMAL CELLS ARE CONTROLLED BY NORMAL STEM
CELLS

5. We have to work for cancer for
• Better understanding of pathophysiology
• Finding out of early / sub clinical stage –
detection.
• Finding out of effective prevention of metastasis.
• Finding out cheap less side effect drugs
• Finding out effective prevention method
• Finding out the cause of relapse and treatment
resistant

6. NEW-CONCEPT OF CANCER
• Healthy cells( simple and stem) have a specific size,
structure, function and growth rate that best serves
the needs of the tissues they compose.
• Cancer cells (somatic and stem) differ from normal
cells in size, structure, function, and growth rate.
• Simple cancer cells differentiates with cancer stem cells
• The malignant cells lack the normal controls of growth
seen in healthy cells, and grow uncontrollably.Cancer
stem cells act as mother cells of cancer somatic cells.

7. General concept OF DISEASE AT
MICRO-MOLECULAR LEVEL
activated NFkB
• Disease( inflammation/vasculitis)=-------------------------
( cancer-stem cell/normal stem cell) IkBa
Persistent stress- inflammation and hypoxia-metabolic
alteration-altered protein synthesis-gene mutation
(immature gene-microRNA)-abnormal-stem cell
physiology- CANCEROUS- INFLAMMAION.

8. Significance of new definition of cancer
• NEW DEFINITION OF CANCER will change
everything about old concept of cancer and
the method of diagnosis, prevention and
treatment of cancer . To
• Helps to carry solution of cancer pollution by
dilution of cancer stem cells.
• Dilution is the solution of pollution.

9. New definition of cancer-BY- Dr.RKD
“It is the process of transformation of normal stem cells
into abnormal (cancer) stem cells due to decreased
matured micro RNA production into the stem cells due
to chronic exposure of any cellular stress factor or
relative low level of antistress factors.”
– Dr. Rajkumar Dhaugoda.
Visiting assistant professor.
China Three Gorges University , Yichang, Hubei
May 1st 2014

10. NORMAL STEM CELL
• Stem cells are undifferentiated biological cells
that can differentiate into specialized cells and
can divide (through mitosis) to produce more
stem cells.
• There are two broad types of stem cells:
embryonic stem cells, which are isolated from the
inner cell mass of blastocysts.
• Adult stem cells, which are found in various
tissues. Umbilical cord blood, bone marrow,
adipose tissue. and other corresponding organ
tissues

11. difference between stem cells and ordinary cells
 self renewal
Stem cells can divide to make exact copies of themselves - a property scientists
call self-renewal.
 They differentiate
Stem cells can differentiate to make specialized cells called progenitor cells that
go on to form the organs and tissues in the human body.
 They duplicate
Every time a stem cell divides, it makes one exact copy and one progenitor cell.
When the progenitor cell divides, it produces two cells that are somewhat more
specialized. Each generation of new cells is more specialized than the previous
generation until, eventually, mature cells are produced.
 They divide indefinitely
Many cells can divide to make copies of themselves, but they can only divide a
certain number of times before they die. Stem cells can keep dividing
indefinitely. Because stem cells are essentially immortal, the body keeps them
under tight control, so they will divide only when a new supply of cells is needed.

12. ADULT STEM CELL
• Every organ and type of tissue in the body
contains a small number of what scientists call
"adult" or "tissue" stem cells.
• Since most cells in the body live for just a
short time, the body needs to keep making
new cells to replace them.
• Adult stem cells ensure a continuous supply
of new cells to replace old cells that wear out
or are destroyed.

13. DEREGULATION OF OF STEM CELL
• Stem cell controls growth of corresponding
somatic cells
• REGULATED BY- MATURE microRNA-
• DECRESEAD LEVEL OF microRNA-
DISREGULATION OF STEM CELL- AND
CAUSING PRODUCTION OF CANCER STEM
CELLS- CAUSED CANCER.

14. TYPES OF STEM CELLS
PRIMITIVE-FETUS/MULTIPOTENT-
CELLS IN AMNIOTIC FLUID/ UMBELICAL BLOOD/ SOMATIC-ADULT
TYPE-UNIPOTENT

15. CANCER STEM CELL
• Cancer stem cells are defined as those cells
within a tumour that can self-renew and drive
tumorigenesis.
• cancer stem cells have been isolated from a
number of human tumours, including
haematopoietic, brain, colon and breast
cancers
• The cancer stem-cell concept has important
implications for cancer therapy

16. CANCER STEM CELL

17. Cancer stem cells
• Cancer stem cells are defined as those cells
within a tumour that can self-renew and drive
tumorigenesis.
• cancer stem cells have been isolated from a
number of human tumours, including
haematopoietic, brain, colon and breast
cancers
• The cancer stem-cell concept has important
implications for cancer therapy

18. 18

19. dialectics
“It is the philosophy, science and methodology
of interrelation and transformation of outer
and inner sets of contradictions of any given
particle, unite, process, phenomena, system
or object” -
Rkdhaugoda

20. X
↕
A↔ ---------- KEY LAW OF DIALECTICS ----↔B
↕
Y
“ In any event, system,objects,process,thought or unit contains an
external set of opposite phenomena which are also connected
relatively by means dynamic reciprocal association with other inner
essence one or more sets of opposite phenomena again”. (It is a
new law explored by Dr. R.K.Dhaugoda in the field of dialectics,
called RK Dhaugoda’s key law of dialectics)
i.e. association of opposite phenomena within opposite phenomena,
systems, which are interdepended,interchangable each other as
four dimensional certain reciprocal associations primarily

21. RK Dhaugoda’s Key law of dialectics
• Here, A and B are outer opposite sets-contained in
every system or events or object or process.
• X and Y are another internal opposite sets’
reciprocally associated with the outer opposite sets
dynamically again

22. The Stem Cell –microRNA Theory of
Cancer- By dr. rk dhaugoda of Nepal
• The stem cell –microRNA theory of cancer
proposes that among all cancerous somatic
cells, a few act as CANCER stem cells due to
decreased matured microRNA production due
to persistent exposure to the any cellular
stress factors or relative decreased level of
cellular anti-stress factors into the stem cells.

23. The Stem Cell –microRNA Theory of Cancer
• APPLICATION OF KEY LAW OF DIALECTICS
• “OPPOSITE PHENOMENA WITHIN OPPOSITE PHENOMENA”-
RKDHAUGODA
1. NORMAL CELL ------- CANCER CELL=OUTER OPPOSITES
2. NORMAL STEM CELL---CANCER stem CELL=INNER OPPOSITES

24. The Stem Cell –microRNA Theory of
Cancer
Normal stem cell
normal cell cancer cell
cancer stem cell

25. The Stem Cell –microRNA Theory of
Cancer
Wnt sig. off in stem cells
Normal stem cell cancer stem cell
Wnt sig. on in stem cells

26. The Stem Cell –microRNA Theory of
Cancer
high level of activated NFkB in stem cell
Wnt sig. off in stem cell Wnt sig. on in stem cells
Relative decreased level of IkBa

27. The Stem Cell –microRNA Theory of
Cancer
activated IKK enzyme in stem cell-by stress factors
activated NFkB in stem cell inactive NFkB in stem cell
Inactive IKK enzyme in stem cell

28. The Stem Cell –microRNA Theory of
Cancer
persistent exposure of various stress factors-
ROS,enviromental,maternal- in stem cell
activated IKK enzyme Inactive IKK enzyme in stem cell
optimum level of prime ANTI-STRESS FACTOR – X-factor stem cell

29. The Stem Cell –microRNA Theory of
Cancer
UPTIMUM LEVEL OF MATURE microRNA
NORMAL STEM CELL CANCER STEM CELL
DOWN REGULATED MATURE micro-RNA

30. Normal gene translation by micro RNA in stem cell
Inactive NFkB activated NFkB in stem cell
abnormal gene translation BY microRNA in stem cell

31. The Stem Cell –microRNA Theory of
Cancer
Down regulated mature –micro RNA
Activation of Myc gene inhibition of Myc gene
(Tumorgenesis)
Optimum level of MATURE micro-RNA

32. The Stem Cell –microRNA Theory of Cancer
DICER AND microRNA
• DICER (contains cyclin dependent kinase)-ACTIVE
Optimum mature microRNA Immature microRNA
( tumor suppressor micro RNA) (oncogenic microRNA)
DICER (contains cyclin dependent kinase)-INACTIVE
(DECREASE PRODUCTION OF MATURE-microRNA)

33. DEREGULATED microRNA –
in cancer stem cell

34. The Stem Cell –microRNA Theory of Cancer
DICER AND microRNA
low level of stem cell stress factor
high level of stem cell anti-stress factor
( normal microRNA level ) ( decreased microRNA
level)
DICER active DICER inactive
( normal stem cell ) ( cancer stem cell )
high level of stem cell stress factor ( NFkB And TNF-alpha)
low level of stem cell anti-stress factor( IkBa And X-factor)

35. Stem cell , micro RNA AND CANCER
• Activated NFKB enters into nucleus of stem cell-
abnormal gene transcription- causing inhibition
of tumor suppressor gene and mutation of proto-
oncogene to form oncogene.
• Thus- wnt target gene activated resulting in and
Abnormal trasformation of stem cells causing
abnormal cell proliferation(tumer- genesis)-that
is production of cancer stem cells.

36. Stem cell , micro RNA AND CANCER
• Activated tumor suppressor protein p53- causes
abnormal stem cell ( beyond repaired )apoptosis
( natural destruction)
• In cancer stem cell p53 –tumor suppressor gene is
inhibited and DNA repair mechanism also damaged
due to inactivation of DNA polymerase –II.

37. Stem cell , micro RNA AND CANCER
• Scientists have identified a new group of culprits that plays a major role in
the development of human cancers. They are tiny bits of ribonucleic acid
(RNA) called microRNAs that control gene activity. In particular, they stop
or slow the production of cellular messengers necessary for division and
growth.
• microRNAs can regulate gene expression and give stem cells a green light
to pass from the normal stop phase to the stage in which they begin
replicating their DNA for later division
• MicroRNAs interact with the Myc gene, an important cell-growth regulator
that appears to be abnormal in as many as half of all tumours, according
to researchers led by Kathryn O'Donnell, a cancer researcher at Johns
Hopkins University School of Medicine in Baltimore. In normal tissues,
Myc prompts production of microRNAs that appear to keep those growth
processes in check by influencing another gene called E2F, said Josh
Mendell, a Johns Hopkins geneticist who co-wrote the study

38. microRNA
• A microRNA ( miRNA) is a small non-coding RNA
molecule (containing about 22 nucleotides) found
in plants, animals, and some viruses, which
functions in transcriptional and post-
transcriptional regulation of gene expression
• The first human disease known to be associated
with miRNA deregulation was chronic
lymphocytic leukemia and later many miRNAs
have been found to have links with some types of
cancer

39. microRNA
• A malfunction in microRNAs may be the cause of a
specific cancer.
• microRNAs and RNA interference in their control over
division of stem cells
• The expression of miRNA seems to be lower in cancer
s than normal tissue .
• Reduced miRNA expression leads to a cancer specific
block and halts in normal development of cells.
• The mature miRNA IS PRODUCED DY DICER (contains
cyclin dependent kinase REGULATES THE miRNA )

40. Signs and Symptoms of Cancer
• Change in bowel habits or bladder functions
• Sores that do not heal
• Unusual bleeding or discharge
• Lumps or thickening of breast or other parts of the body
• Indigestion or difficulty swallowing
• Recent change in wart or mole
• Persistent coughing or hoarseness
• Not having symptoms does not mean there is no cancer.
• Initiation of cancer is a long and abnormal complex intracellular
processes in stem cells with lower level expression of microRNA.
• So- if there are low level of specific mature microRNA in blood or
cells or tissue –may be various degree of sub clinical cancer.

41.  Carcinomas (cells
that cover internal and
external body surfaces)
Types of Cancers
Lung
Breast
Colon
Bladder
Prostate
(Men)
Leukemia
(Blood Cells)
Lymphomas
(Lymph nodes &tissues)
Sarcomas
Cells in supportive
tissues – bones &
muscles

42. TERMINOLOGY
• CANCER
• Neoplasia
• Neoplasm
• Metaplasia
• displasia
• Carcinogens
• Carcinogenesis
• Apoptosis
• Oncogene
• Proto-oncogenes
• Tumor suppressor gene
• mutation
• TUMOR
• BENIGN
• MALIGNANT
• Stress factors- viruses, parasites,
radiations,
• METASTASIS
• CHEMOTHERAPY
• RADIOTHERAPY
• immunotherapy
• Palliative care
• staging
• Prognosis
• TNF-alpha
• IkBa
• NFkB
• IKK
• TELOMERE
• STAGING
• ANTI-CANCER DRUG CLASSIFICATIONS
• GLYCOLYSIS
• Stem cell
• Cancer stem cell
• microRNA
• PET- SCAN
• TUMOR MARKERS
• Anti-cancer drugs

43. benign tumor
• A benign tumor is a mass of cells (tumor) that lacks the
ability to invade neighboring tissue or metastasize.
These characteristics are required for a tumor to be
defined as cancerous and therefore benign tumors are
non-cancerous. Also, benign tumors generally have a
slower growth rate than malignant tumors and the
tumor cells are usually more differentiated (cells have
normal features). Benign tumors are typically
surrounded by an outer surface (fibrous sheath of
connective tissue) or remain with the epithelium.[4]
Common examples of benign tumors include moles
(nevi) and uterine fibroids (leiomyomas).

44. Two major types: Benign and
Malignant
Benign:grow slowly
1) low mitotic rate
2) well differentiated
3) not invasive; well-defined borders
4) remain localized;
5) do not metastasize

45. malignant
• Malignancy (from Latin male "badly" + -gnus
"born") is the tendency of a medical
condition,
• especially tumors, to become progressively
worse and to potentially result in death.
Malignancy in cancers is characterized by
anaplasia, invasiveness, and metastasis.

46. 46
Stages of cancer spread:
Stage 1 – confined to site of origin
Stage 2- cancer is locally invasive
Stage 3 – cancer has spread to
regional structures
Stage 4- cancer has spread to
distant sites

47. Modes of cancer Therapy
• Surgery- curative/palliative
• Radiation-
• Chemotherapy
• Immunotherapy -interferon or interleukins
• Antibodies-TNF-alpha-inhibitors
• IKK- enzyme inhibitors
• Small molecules-proteins- that activates the DICER-enzyme
• Adjunctive-anti-inflammatory-thalidomide.
• Stem cell- implantation/transplantation
• Supplement of IkBa agonists
• Supplement of microRNA agonists
• Drugs for killing of cancer stem cells of tumor

48. CARCINOMA OF LUNG/bronchial
carcinoma
• malignant lung tumor characterized by
uncontrolled cell growth in tissues of the lung.
• Most cancers that start in the lung, known as
primary lung cancers, are carcinomas that derive
from squamous epithelial cells/ mucus gland
• The main primary types are-squamous cell
carcinoma,adenocarcinoma, small-cell lung
cancer (SCLC), also called oat cell cancer, and
large cell carcinoma

49. Ca- lung
• Lung cancer is a common disease that has a
poor prognosis.
• Survival is inversely proportional to the stage,
with early detection and diagnosis being the
key to achieving surgical cure.
• Cross-sectional imaging is now the main
radiological means of assessment.

50. Types of lung cancer
two major types based on the appearance of lung cancer cells under the microscope
The two general types of lung cancer include:
A. Small cell lung cancer.
Small cell lung cancer occurs almost exclusively in
heavy smokers and is less common than non-small
cell lung cancer.
B. Non-small cell lung cancer.
Non-small cell lung cancers include squamous cell
carcinoma, adenocarcinoma and large cell
carcinoma

51. Clinical features
• The most common symptoms are coughing
(including coughing up blood), weight loss,
shortness of breath, and chest pain.
• Supra-clavicular nodes may be present.
• Digital clubbing.
• signs due to large tumor compression- wheeze
,creps , decreased air entry.
• signs of pleural effusion.

52. Major cause- smoking
• The most common cause is long-term
exposure to tobacco smoke, which causes 80–
90% of lung cancers. Cigarette smoke contains
over 60 known carcinogens.
• Nonsmokers account for 10–15%
• exposure to; radon gas, asbestos, and air
pollution including PASSIVE smoking

53. Other causes- Ca lung
• Some metals (aluminum production, cadmium and cadmium
compounds, chromium(VI) compounds, beryllium and beryllium
compounds, iron and steel founding, nickel compounds, arsenic and
inorganic arsenic compounds, underground hematite mining)
• Some products of combustion (incomplete combustion, coal
(indoor emissions from household coal burning), coal gasification,
coal-tar pitch, coke production, soot, diesel engine exhaust)
• Ionizing radiation (X-radiation, radon-222 and its decay products,
gamma radiation, plutonium)
• Some toxic gases (methyl ether (technical grade), Bis-(chloromethyl)
ether, sulfur mustard, MOPP (vincristine-prednisone-nitrogen
mustard-procarbazine mixture), fumes from painting)
• Rubber production and crystalline silica dust

54. Chest x-ray
• an obvious mass ( coin lesion),
• widening of the mediastinum (suggestive of
spread to lymph nodes there),
• atelectasis (collapse),
• consolidation (pneumonia),
• pleural effusion

55. INVESTGATIONS
Confirm diagnostic should be done by biopsy
• BLOOD TESTS-
• INVESTIGATIONS TO RULE OUT –PTB
• CHEST-X-RAY- EFFUSION/ OPAQUE COIN LESION
• SPUTUM CYTOLOGY
• BRONHOSCOPY- BAL / BIOPSY-HPE
• FNAC-
• THORACOSCOPY
• USG- ABDOMEN- TO SEE PLERAL EFFUSION.
• Tumor markers-M2-PK, other- CEA, CA 19-9, CA 125
• micro-RNA

56. Early diagnosis- of cancer
• Exosomal microRNA: a diagnostic marker for lung
cancer
• MicroRNAs (miRNAs) are a class of small
noncoding RNA genes found to be abnormally
expressed in several types of cancer, suggesting a
role in the pathogenesis of human cancer.
Clin Lung Cancer. 2009 Jan;10(1):42-6. doi:10.3816/CLC.2009.n.006.
Exosomal microRNA: a diagnostic marker for lung cancer.
Rabinowits G1, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH.

57. A NEW TUMOR MARKER
FOR LUNG CANCER-IDH1
• A protein called isocitrate dehydrogenase
(IDH1) is present at high levels in lung cancers
and can be detected in the blood, making it a
noninvasive diagnostic marker for lung
cancers, according to a study published in
Clinical Cancer Research, a journal of the
American Association for Cancer Research.

58. Imaging for Ca- lung
• Chest X-ray is still important, and frequently
suggests the first diagnosis.
• CT is MORE ACCURATE THAN- CHEST X-RAY
• MRI- is More accurate than CT
• Currently there is little to choose between CT and
MRI in staging the disease although CT is more
widely available and less expensive.
• PET imaging offers heightened sensitivity for
both detection of the primary malignancy and
disease spread, although it is not 100% accurate
and is only available in a few centers.