New definition and new theory (stem cell-microRNA Theory) of cancer-by dr.rajkumar dhaugoda of...

Lecture notes on New definition and new theory (stem cell-microRNA Theory) of cancer

General concept of cancerBy Dr.Rkdhaugoda

CTGU, YICHANG CHINA-Visiting Assistant professor ( FROM NEPAL)

2014- MAY-5th

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.

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.

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

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

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.

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.

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.

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

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

difference between stem cells and ordinary cells

self renewalStem cells can divide to make exact copies of themselves - a property scientists call self-renewal.

They differentiateStem cells can differentiate to make specialized cells called progenitor cells that go on to form the organs and tissues in the human body.

They duplicateEvery 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 indefinitelyMany 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.

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.

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.

TYPES OF STEM CELLSPRIMITIVE-FETUS/MULTIPOTENT-

CELLS IN AMNIOTIC FLUID/ UMBELICAL BLOOD/ SOMATIC-ADULT TYPE-UNIPOTENT

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

CANCER STEM CELL

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

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

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

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

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.

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 OPPOSITES2. NORMAL STEM CELL---CANCER stem CELL=INNER OPPOSITES


Normal stem cell

normal cell cancer cell

cancer stem cell


Wnt sig. off in stem cells

Normal stem cell cancer stem cell

Wnt sig. on in stem cells


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


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


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


UPTIMUM LEVEL OF MATURE microRNA

NORMAL STEM CELL CANCER STEM CELL

DOWN REGULATED MATURE micro-RNA

Normal gene translation by micro RNA in stem cell

Inactive NFkB activated NFkB in stem cell

abnormal gene translation BY microRNA in stem cell


Down regulated mature –micro RNA

Activation of Myc gene inhibition of Myc gene (Tumorgenesis)

Optimum level of MATURE micro-RNA

The Stem Cell –microRNA Theory of CancerDICER 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)

DEREGULATED microRNA –in cancer stem cell

The Stem Cell –microRNA Theory of CancerDICER 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)

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.

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.

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

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

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 )

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.

Carcinomas (cells that cover internal and external body surfaces)

Types of Cancers

Lung

Breast

Colon

BladderProstate (Men)

Leukemia(Blood Cells)Lymphomas(Lymph nodes &tissues)

SarcomasCells in supportive tissues – bones & muscles

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

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).

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

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.

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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

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

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

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.

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

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.

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

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

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

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

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.

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.

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.

New definition and new theory (stem cell-microRNA Theory) of cancer-by dr.rajkumar dhaugoda of...

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