Molecular Basis of Cancer (Carcinogenesis)

Basic principles of carcinogenesis:

The fundamental principles in carcinogenesis include

1)  Non-lethal genetic damage lies at the heart of carcinogenesis. Such genetic damage (mutation) may be acquired by the action of environmental agents such as chemicals, radiation or viruses or it may be inherited in the germ line.

2)  The three classes of normal regulatory genes are:

i) The growth promoting proto-oncogenes

Activation of proto-oncogenes activation gives rise to oncogenes (cancer causing genes).Proto

- oncogenes are activated by  

- Point mutation

- Chromosomal rearrangements ranslocation Inversion 

- Gene amplification

ii) Cancer suppressor genes (anti oncogenes) 

-  Its physiologic role is to regulate cell growth however, the inactivation of cancer suppressor genes is the key event in cancer genesis 

-  Examples of tumour suppressor genes  include-Rb, P53, APC and NF-1&2 genes

iii) Genes that regulate apoptosis

-  Genes that prevent or induce programmed cell death are also important variables in the cancer equation. These genes include bcl-2 that inhibits apoptosis whereas, others such as bax.  Bad, and bcl-x5 favour programmed cell death. Genes that regulate apoptosis may be dominant as are proto-oncogenes or may behave as cancer suppressor genes (recessive in nature) iv) Genes that regulate DNA repair ƒ  Inability to DNA repair can predispose to mutations in the genome and hence, to neoplastic transformations

3)  Carcinogenesis is a multifactorial process 

-  at both the phenotypic and genotypic levels.

Types of carcinogenesis:

 A large number of agents cause genetic damages and induce neoplastic transformation of cells. They fall into the following three categories:

 a) Chemical carcinogenesis

b) Radiation carcinogenesis

c) Viral carcinogenesis

A) Chemical carcinogenesis

  An enormous variety of chemicals may induce tumours and this was exemplified by Sir Percival Pott’s observation in the last century that astutely related the increased incidence of scrotal skin cancer in chimney sweeps to chronic exposure to soot.

Steps involved in chemical carcinogenesis 

-  appropriate dose of a chemical carcinogenic agents to a cell results in the  formation of initiation –promotion sequence

-  Initiation causes permanent DNA damage (mutation) which, is rapid and irreversible.

However, initiation alone is not sufficient for tumour formation and thus, promoters can induce tumours in initiated cells, but  they are non-tumourogenic by themselves.  Furthermore, tumours do not result when a promoting agent applied before, the initiating agent. 

-  In contrast to the effects of initiators, the cellular changes resulting from the application of promoters do not affect DNA directly and are reversible. 

- Promoters render cells susceptible to  additional mutations by causing cellular proliferation. Examples of promoters include phorbol ester, hormones, phenols and drugs. 

Chemical carcinogenic agents fall into two categories 

1.  Directly acting compound 

-  These are ultimate carcinogens and have one property in common:

-  They are highly reactive electrophiles (have electron deficient atoms) that can react with nucleophilic (electron-rich) sites in the cell. This reaction is non-enzymatic and result in the formation of covalent adducts (addition products) between the chemical carcinogen and a nucleotide in DNA.

-  Electrophilic reactions may attack several electron-rich sites in the target cells including DNA, RNA, and proteins.

-  Only a few alkylating and acylating agents are directly acting carcinogens 

2.  Indirect acting compounds (or pro-carcinogens)

-  Requires metabolic conversion in vivo to produce ultimate carcinogens capable of transforming cells.

-  Most known carcinogens are metabolized by cytochrome p-450 dependent mono-oxygenase.

-   Examples of this group include polycyclic and heterocyclic aromatic hydocarbones, and aromatic amines etc….

-  These chemical carcinogens lead to mutations in cells by affecting the functions of oncogenes, Oncosupressor genes and genes that regulate apoptosis.  

B) Radiation carcinogenesis

Radiant energy whether in form of ultraviolet  (UV) sun light or ionizing electromagnetic (X rays and gamma (δ ) rays) and particulates (α,β, protons and neutrons) radiation can transform and induce neoplasm in both humans and experimental animals.

Two types of radiation injuries are recognized:

 i) Ultraviolet rays (UV light) 

-  UV rays are examples of non-ionizing radiation that cause vibration and rotation of atoms in biologic molecules

-  UV rays induce an increased incidence of squamous cell carcinoma, basal cell carcinoma and possibly malignant melanoma of skin.

-   Risk factors for developing UV rays related disorders depend on

   * Type of UV rays – UV type B

    * Intensity of exposure

   * Quality of light absorbing “protective mantle” of melanin in the skin

     Ex. Australians (queen's land etc.) 

-  UV rays’ effects on cell nucleus are: 

    * The carcinogenesis of UV type B rays is attributable to its formation of pyrimidine dimmers in DNA

   * However, UV rays can also cause inhibition of cell division,   inactivation of enzymes, Induction of mutation and sufficient dose kill cells.

As with other carcinogens, UVB also cause mutations on oncogenes and tumour suppressor genes mutant forms of P53 and ras genes have been detected.

ii) Ionizing radiation

-  Ionizing radiations are of short wave lengh and high frequency which can ionize biologic target molecules and eject electrons 

-  Electromagnetic and particulate radiations in forms of theureptic, occupational or atomic bomb incidents can be carcinogenic  

-  Occupational hazards include:

Many of the pioneers in the development of roentegen rays develop skin cancers. Miners for radioactive elements---lung cancer

-  Therapeutic irradiations have been documented to be carcinogenic. Thyroid cancer may result from childhood & infancy irradiation (9%), and by the same taken radiation therapy for spondylitis may lead to a possible acute leukemia year later.

-  In atomic bonds dropped in Hiroshima and Nagasaki initially principal cancers were acute and chronic mylogenous leukemias after a latent of about 7 years solid tumours such as breast, colon, thyroid and lung cancers) increased in incidence.

-  In humans, there is a hierarchy of vulnerability of radiation-induced cancers. Most frequent are the leukemia except CLL, which almost never follow radiation injury. Cancer of the thyroid follows closely but only in the young. In intermediate category are cancers of the breast, lungs, and salivary glands 

-  In contrast, skin, bone and gastrointestinal tract are relatively resistant to radiation-induced neoplasia.

C) Viral and bacterial carcinogenesis  

Large groups of DNA and RNA viruses have proved to be oncogenic and there is an association between infections by the bacterium Helicobacter Pylori and gastric lymphoma.

 i) DNA oncogenic viruses

This group includes: 

Human Papilloma Virus (HPV)

Epstein Barr Virus (EBV)

Hepatitis B Virus (HBV)   

General feature of the oncogenic DNA virus 

a) Transforming DNA virus form stable associations with the host cell genome. The integrated virus is unable to complete its replicative cycle because the viral genes essential for completion of replication are interrupted during integration of viral DNA (E1/E2) 

b) Those viral genes that are transcribed early  (early genes) in the viral life cycle are expressed in the transformed cells.

Human papilloma Virus (HPV)

-  HPV definitely causes benign squamous papilloma (warts) (type 1,2,3,4, 7). It also implicated in the genesis of squamous cell  carcinomas of cervix and anogenital region (types 16,18 and also 31,33,35,and 51 found in 85% SCC). It is also linked to the causation of oral and laryngeal cancers. 

-  The HPV DNA integration into host cell is random (viral DNA is found in different locations), however, the pattern of integration, is clonal (that is the site of integration is identical within all cells of a given cancer).

Epstein – Barr virus (EBV)

-  Member of the herpes family has been implicated in the pathogenesis of four tumours. The African form of Burkitt's lymphoma,  B- cell lymphomas in immuno suppressed individuals particularly in those with some cases of Hodgkin’s disease and Naso pharyngeal carcinoma.

-  EBV infects epithelial cell of the oro pharynx and B- lymphocytes. The infection of B- cell is latent and the latently infected B-cell is immortalized. Several viral genes dysregulate the normal proliferative and survival signals in latently infects cells for example the latent membrane protein –1 (LMP-1) prevents apoptosis of B- cells by up regulating the expression of bc1-2 and it activates growth promoting pathways. Thus, LMP-1 can induce both cell growth and cell survival. Similarly the EBV- encoded EBNA- gene transactivates several host genes including cyclin D and members of the src family EBNA- 2  also activates the transcription of LMP- 1. Thus, it seems that several  viral genes collaborate to render B- cells immortal.

-  The Association between African Burkett Lymphoma and EBV is    quite strong.

•  More than 90% of African tumours carry the EBV genome

•  One hundred percent of the patients have elevated antibody titres against viral capsid antigens

•  Serum antibody titres against viral capsid antigens are correlated  with the risk of developing the tumour. Several other observations suggested that additional factors must be involved. In Africa poorly understood co-factor (ex chromic malaria), favor sustained proliferation of B- cells immortalized by EBV. The actively dividing B- cells are at increased risk of mutations (t- 8; 14) translocation that juxta - pose C- myc with one of Immuno- globuline gene loci.

 Hepatitis B- virus (HBV)

- Strong epidemiologic association prevails between HBV and hepato cellular Carcinoma. HBV genome, however, does not encode any oncoproteins, and there is no consistent pattern of integration in the vicinity of any known protomcogeres

-  The effects of HBV is indirect and possibly multi factorial. 

i) By causing chronic liver cell injury and accompanying regenerative hyperplasic

ii) HBV encodes a regulatory element called HBx protein, which disrupts normal growth control of infected liver cells by transcriptional activation of several growth promoting genes such as insulin like growth factor II

iii) HBV binds to P53 and appears to interfere with its growth suppressing activities. Although not a DNA virus hepatitis virus is also strongly linked to the pathogenesis of hepato cellular carcinoma as evidenced by epidemiologic studies.

ii. RNA oncogenic viruses

-  Although the study of animal retroviruses has provided spectacular insights to molecular basis of cancer , only one retrovirus is firmly implicated in the causation of cancer and it is Human T cells leukemia/ lymphoma virus type 1 (HTLV-1) .

-  Similar to HIV virus. HTLV-1 has tropism for CD4+T cells > Human infection requires transmission of infected T cells through sexual intercourse, blood products, or breast feedings. Leukemia develops after a 20 or 30 years of latency in about 1% of patients. HTLV-1 is also associated tropical spastic Para paresis.

iii. Helicobacter pylori 

-  There is an association between gastric infections with helicobacter pylori as a cause of gastric lymphoma. The stronger link is with B cell lymphoma of stomach. Treatment of H. pylori with antibiotics results in regression of the lymphoma in most cases. The lymphoma arise from the mucosa associated lymphoid tissues (MALT) hence, they sometimes are called MALTOMAS. The lymphoid cells reside in the marginal zones of lymphoid follicles and hence alternatively named as mantle zone lymphoma.  

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.