The document discusses various theories of cancer causation that have been proposed over the centuries. It describes early theories such as the humoral theory, lymph theory, and blastema theory. It then discusses major 20th century theories including the cellular theory, biochemical theory, noxious theory, somatic theory, and regulatory theory. Key concepts of theories like the multistep theory, mutagenesis theory, epigenetics theory, oncogene hypothesis, tumor suppressor gene theory, and cancer stem cell hypothesis are summarized. The document also discusses Knudsen's two-hit theory and theories of immunosurveillance and immunoediting.

1. Theories of cancer
causation
PREPARED BY
MS. THEERTHA P KRISHNA
IIND YEAR MSC NURSING
MIMS CON

2. INTRODUCTION
•Several theories and hypothesis have been proposed to explain
how and why cancer occurs from a continuum spanning
tumorigenesis to metastasis.
•Theories of carcinogenesis devised in the course of the last two
centuries reflects the progress of insight from the cellular level via
biochemistry to an understanding of damaging influences and
oncogenes and to more wholistic approach in the regulatory
theory.

3. EARLY THEORIES OF CANCER CAUSES
Humoral Theory
Lymph Theory
Blastema Theory
Chronic Irritation Theory
Trauma Theory
Infectious Theory

4. HUMORAL THEORY
•Hippocrates believed that the body had 4 humors (body fluids): blood,
phlegm, yellow bile, and black bile.
•The belief was that too much or too little of any of the humors caused
disease.
•An excess of black bile in various body sites was thought to cause
cancer.

5. LYMPH THEORY
•Stahl and Hoffman theorized that cancer was composed of
fermenting and degenerating lymph, varying in density, acidity,
and alkalinity.
•The lymph theory gained rapid support. John Hunter, the
Scottish surgeon from the 1700s, agreed that tumors grow from
lymph constantly thrown out by the blood.

6. BLASTEMA THEORY
•In 1838, German pathologist Johannes Muller demonstrated that cancer
is made up of cells and not lymph, but he believed that cancer cells did not
come from normal cells.
•Muller proposed that cancer cells developed from budding elements
(blastema) between normal tissues.
•His student, Rudolph Virchow (1821-1902), the famous German
pathologist, determined that all cells, including cancer cells, are derived
from other cells.

7. CHRONIC IRRITATION THEORY
•Virchow proposed that chronic irritation was the cause of cancer, but he
believed incorrectly that cancers “spread like a liquid.”
•In the 1860s, German surgeon, Karl Thiersch, showed that cancers
metastasize through the spread of malignant cells and not through some
unidentified fluid.

8. TRAUMA THEORY
•From the late 1800s until the 1920s, trauma was thought by some to
cause cancer.
•This belief was maintained despite the failure of injury to cause cancer in
experimental animals.

9. INFECTIOUS THEORY
•Zacutus Lusitani (1575-1642) and Nicholas Tulp (1593-1674), 2 doctors
in Holland, concluded at almost the same time that cancer was
contagious.
•They made this conclusion based on their experiences with breast cancer
in members of the same household.
•Lusitani and Tulp publicized the contagion theory in 1649 and 1652,
respectively.
• They proposed that cancer patients should be isolated, preferably outside
of cities and towns, in order to prevent the spread of cancer.

10. OTHER MAJOR THEORIES
Cellular Theory
Biochemical Theory
Noxious Theory
Somatic Theory
Regulatory Theory

11. CELLULAR THEORY
•In 1665, Robert Hooke described walled cavities in his microscopic
examination of cork and called them cells.
•Between 1850 and 1855, he extended these observations to embryonic
development and proposed that tumor cells arose by cell formation
from existing specific tissues.
•Virchow had been a student of Müller’s, who had demonstrated in
1838 that cancer is made up of cells, not lymph; but he was of the
opinion that cancer cells arose from interstitial budding elements,
blastema, not from normal cells). Hence, tumors are derived from cells
that divide faster than they should.

12. CELLULAR THEORY
• Generally, the human tumor cells that grow permanently in culture are a selected
group of very aggressive cancers. Almost all of the continuous cell lines are derived
from high-grade, high-stage cancers.
• Programmed cell death (apoptosis, Greek: falling off of tree leaves) may be
invoked by many organisms as a control mechanism to prevent unrestricted
growth.
• For the first time, it was demonstrated that the pathway to tumorigenesis
depends not only on the ability to escape growth control but also on the ability to
prevent cell death.

13. BIOCHEMICAL THEORY
•According to the biochemical theory of cancer, various aspects of
metabolism may be affected in a manner that could lead to cancer.
•During tumor progression, the enzymatic composition of the affected cells
is simplified (described as the theory of convergence in cancer), so that
various cancers resemble one another more than they resemble their tissue
of origin.
•Carcinogenesis resulted from permanent alterations or loss of proteins that
are essential for the control of growth.

14. BIOCHEMICAL THEORY
•Thus, carcinogens eliminate specific enzymes from the affected cells by
binding covalently to water-soluble basic proteins (h2 proteins according
to electrophoresis nomenclature).
•This causes the elimination (deletion) of these proteins from the cells.
Cancer originates because the water-soluble basic proteins contain several
growth inhibitory components.
•Therefore, the initial step in carcinogenesis is the inactivation of
endogenous inhibition.

15. NOXIOUS THEORY
•The insight that malignancy may be caused by the influence of
damaging agents forms the basis of the noxious theory of carcinogenesis.
• Among the influences that may cause cancer are chemicals, radiation,
and viruses.

16. A. Chemical carcinogenesis
•Certain occupations are associated with high levels of exposure to
specific carcinogenic influences. These agents cause DNA damage
through physical or chemical effects.
•During the following years of the 20th century, chemical carcinogenesis
by tobacco products became a major cause for an increasing incidence of
lung cancers.
•Nasopharyngeal cancer is among the most widespread tumors in
Southeast Asia, possibly supported by the ingestion of salted fish.
Esophageal cancer typically occurs in conjunction with alcoholism.

17. B. Radiation carcinogenesis
• Marie Curie discovered the element radium, as well as methods for separating
radium from radioactive residues in sufficient quantities to analyze its
therapeutic properties.
• After a life time of research into radioactivity, Marie Curie succumbed to pre-
leukemia.
• The hazards of exposure to ionizing radiation were soon recognized. Acute skin
reactions were observed in many individuals working with the recently invented
X-ray generators.
• Radiation of charged particles (α-rays, electron rays including β-rays, proton
rays) bear a higher risk for cellular damage, including transforming events

18. C. Viral carcinogenesis.
• In general, the infection of cells with an oncogenic DNA virus may result either in
productive lytic infection with cell death and the release of newly formed virus
particles or in cell transformation to the neoplastic state with little or no virus
production, but with the integration of viral genetic information into the cell
DNA.
• The viral genes capable of causing transformation (viral oncogenes) typically
belong to the latent group of genes, which allow the infected cells to stay alive.
The viral oncogenes are then present in all of the resulting cancer cells.

19. C. Viral carcinogenesis
•Viral transforming genes are collectively called v-onc, and their normal
cellular counterparts are collectively referred to as c-onc
•DNA tumor viruses encode oncogenes of viral origin that are essential
for viral replication and cell transformation.
•The long delay between infection and the occurrence of tumors suggested
that viruses can act in tumor initiation, and that additional damaging
influences are required for tumor promotion.

20. •Oncogenic DNA Viruses. Three major families of DNA viruses,
including herpes viruses, hepadna viruses, and papilloma viruses, have
oncogenic potential.
•Oncogenic RNA Viruses: Among the many families of RNA viruses,
only members of the retrovirus and flavivirus families are capable of
transforming cells and inducing tumors

21. SOMATIC THEORY
• Theodor Boveri (1862–1915) proposed that defects in chromosomes lead to
malignancy. He hypothesized that malignant tumors might be the result of a
certain abnormal condition of the chromosomes, which may arise from multipolar
mitosis. The main concepts of Boveri’s theory are:
 The problem of tumors is a cellular problem
 Typically, every tumor arises from a single cell
 The primordial cells of tumors contain, as a result of an abnormal process,
definite and wrongly combined chromatin contents
 Chromosome abnormalities are the cause to the tendency toward rapid cell
proliferation, which is passed on to all decendents of the primordial cell

22. SOMATIC THEORY
•Tumor initiation and progression occurs through the accumulation of
changes that begin when a single normal cell sustains a permanent
genetic damage.
•The resulting dysregulation of gene function is responsible for the clonal
expansion of a population of somatic cells that ultimately becomes
dominant.

23. REGULATORY THEORY
•The regulatory theory contends that cancer is not a morphologic entity,
but an aberrant regulatory process among individual cells, their
microenvironment, and the entire host.
•In malignant cells, the normal balance between the number of cells
completing the cell cycle and the number of cells dying is changed

24. Major Theories Of Tumorigenesis
• Theory of clonal expansion
• Multistep theory
• Mutagenesis theory
• Epigenetics theory
• Oncogene hypothesis theory
• Tumor suppressor gene theory
• Knudsen’s two hit theory
• Cancer stem cell hypothesis theory
• Immunosurveillance theory

25. THEORY OF CLONAL EXPANSION
• Nowell’s Clonal evolution theory holds that cells within a particular tumor must
at some point have had the same genetic makeup and been homogeneous.
• Initiation of this clone of cancer cells may involve a stem cell that is already
dividing.
• During successive mitotic divisions of this cell, the lineage fails to proceed to
differentiation.
• Uncontrolled proliferation may be accompanied by morphological and biochemical
changes and/or altered gene expression in early cancer cells.

27. MULTISTEP THEORY

28. a. Initiation
•Cancer cells arise from normal cells as a result of changes in genes.
•The first stage, initiation involves a mutation in the cells genetic
structure.
•Cancer producing carcinogens are capable of producing cell alterations.
•Carcinogens enter the cell nucleus and alter DNA.

29. b. Promotion
•Promotion the second stage in the development of cancer is characterized
by the reversible proliferation of the altered cells.
•Promoting factors include agents such as dietary fat, obesity, cigarette
smoking and alcohol consumption.
•For example, cigarette smoking is a promoting agent in bronchogenic
carcinoma.

30. c. Progression
•Progression is the final stage in the natural history of a cancer.
•This is characterized by increased growth rate of tumor, increased
invasiveness and metastasis.
•Tumor cells are able to detach from the primary tumor, invade the tissue
surrounding the tumor and penetrate the walls of the lymph or vascular
vessels for metastasis to a distant site.

32. MUTAGENESIS THEORY
•Cancer arises through a series of somatic alteration in DNA, that result
in cellular proliferation.
•Nearly all cancers originate from a single cell, this clonal origin is critical
discriminating feature between neoplasia and hyperplasia.
•It is believed that five to ten accumulated mutation are necessary for a
cell type to progress from the normal to the fully malignant phenotype.

34. EPIGENETICS THEORY
•Epigenetics’ is defined as the inheritable changes in gene expression with
no alterations in DNA sequences.
•Epigenetic mechanisms are required to maintain normal growth and
development and gene expression in different organs.
•Abnormal epigenetic regulation may alter gene expression and function
which may lead to diseases such as cancer.
•Human tumors, in essence, are a genetic disease, since during cancer
formation, a large number of genes are mutated or abnormally activated.

35. EPIGENETICS THEORY
•Carcinogenesis also involve epigenetic changes such as DNA methylation,
histone modifications and microRNAs
•These molecular alterations lead to permanent changes in the patterns of
gene expression that regulate the neoplastic phenotype, such as cellular
growth and invasiveness.

36. ONCOGENE HYPOTHESIS THEORY
•Proto-oncogenes are genes that normally help cells grow. When a proto-
oncogene mutates (changes) or there are too many copies of it, it becomes
a "bad" gene that can become permanently turned on or activated when it
is not supposed to be.
• When this happens, the cell grows out of control, which can lead to
cancer. This bad gene is called an oncogene.
•The theory of oncogenes was foreshadowed by the German
biologist Theodor Boveri is called an oncogene.

37. ONCOGENE HYPOTHESIS THEORY
• Theory of oncogenes in which he predicted the existence of
oncogenes that become amplified during tumor development.

38. TUMOR SUPPRESSOR GENE THEORY
•Tumor suppressor genes make proteins that regulate the growth of cells,
and they play an important role in preventing the development of cancer
cells.
•When tumor suppressor genes are altered or inactivated due to a
mutation (either one that is present at birth or one that occurs later in
life), they make proteins that are less effective at controlling cell growth
and/or repair. The result is unchecked growth of damaged or abnormal
cells, which leads to uncontrolled growth and the development of
cancerous tumors.

39. TUMOR SUPPRESSOR GENE THEORY
•RB: The suppressor gene responsible for retinoblastoma.
•p53 gene: The p53 gene creates protein p53 which regulates gene repair in
cells.
•BRCA1/BRCA2 genes: responsible for around 5 percent to 10 percent of
breast cancers.
•APC gene: These genes are associated with an increased risk of colon
cancer.

40. KNUDSEN’S TWO HIT THEORY
• A geneticist and physician, Dr. Knudson (August 9, 1922 – July 10, 2016) was
internationally recognized for his "two-hit" theory of cancer causation, which
explained the relationship between the hereditary and non-hereditary forms of a
cancer and predicted the existence of tumor-suppressor genes that can suppress
cancer cell growth.

41. KNUDSEN’S TWO HIT THEORY

42. CANCER STEM CELL HYPOTHESIS THEORY
•Tumors are functionally heterogeneous and hierarchical.
•They are composed of cells that can initiate tumors (tumor initiating cells
or cancer stem cells) and cells that arise from CSCs but cannot initiate
tumors.
•The frequency of CSC in a tumor is highly variable (often low).
•Cancer stem cells may have different sensitivities to radiation or
chemotherapy. Therefore, the concept of CSCs has significant clinical
implications.

43. CANCER STEM CELL HYPOTHESIS THEORY

44. CANCER STEM CELL HYPOTHESIS THEORY

45. IMMUNOSURVEILLANCE THEORY
•Immunoediting is a theory that describes the transformation of normal
cells to clinically-detectable cancer. The theory implies that while the
human immune system protects from cancer, it also drives the
development of tumors that will undergo immunogenic “sculpting” and
may survive immune cell attacks. Proposed by Gavin P. Dunn, MD,
PhD, and Robert Schreiber.
•The immunoediting process consists of three phases, often referred to as
the “3 es”: elimination, equilibrium and escape.

46. IMMUNOSURVEILLANCE THEORY

47. Elimination
•Both innate and adaptive immune cells play a role in immune
surveillance. In this phase, growing tumors are completely eliminated by
the immune system.
•Immune surveillance is the first phase (elimination) of the
immunoediting process

48. Equilibrium
•Some cancer cells may not be controlled by the innate and adaptive
immune cells during elimination.
•When this occurs, the cells able to survive elimination replicate with new
variants that may be more resistant to the immune response.
•During this phase, cancer remains clinically undetectable and is dormant.

49. Escape
•In this phase, cancer cells have escaped the immune system and are
replicated, leading to clinically detectable tumors.

50. CONCLUSION
•There is no single cause of cancer.
•Scientists believe that it is interaction of many factors together that
produces cancer.
•The factors involved may be genetic, environmental or constitutional
characteristics of individuals.