CANCER:  collected notes thereon

 

Carcinoma arises from the

epithelial cells (covering the

surface).

SARCOMA:  arising from connective

tissue or muscle cells.

LEUKEMIA:  arising from

hemopoietic cells.

 

OVERVIEW:  There are 10 to the

16^th power cell divisions taking

place in the human body in the course of a lifetime (for mice 10 to the 12th).[i]   In a free of mutagen environment there is mutation rate per gene per cell division is one in a million, that means that in each cellular reproduction, the DNA of a particular gene (which has about a hundred letter) this gene has a 1 in a million chance of being inaccurately copied,[ii] but there are 65 trillion cells reproducing.  Thus during a lifetime there will be 10 to the 10^th power accumulation of mutations in the cells with a mutation of one of their genes, which equates to one cell in 650 having a mutation of a particular gene.  Not all mutations are equally devistating, and most of the genes are recessive, thus most of the mutations are to recessive genes.  

 

Three to seven random events are required for cancer, three being for leukemia.  Thus for example the rate of cancer rose sharply for smokers after 10 or 20 years, while for leukemia only after 5 years and peaked after 8 years. The same 10, 20 or more years is common for occupational carcinogens.  The process of mutation translates into 560,000 deaths (6.6 million world-wide) from cancer each year in the United States, and 1.4 million new cases.  Cancer accounts for about 25% of the total deaths in developed countries. 

 

 

For CHRONIC MYELOGENOUS LEUKEMIA, distinguished by the Philadelphia chromosome, created by the translocation between the long arms of chromo­some 9 and 22.  For a patient the location of such translocation is the same, but when compared to different patients the location differs from several hundred to over a thousand base pairs, thus showing that one mutation event gave rise to the leukemia.  Other mutation events are required for the mutation to prove fatal.  The disease begins as a non-­lethal, overproduction of white cells and continues for several years before changing and causing death within a few months, usually.

 

UTERINE CERVIX CANCER is of the epithelium.  DYPLASIA, where patches of cells are no longer confined to the basal layer and there is some disorder in the process of differentiation. Dysplastic patches often remain harmless, some even spontaneously regress, rarely the patches give rise to carcinoma in situ.  In Dysplastic patches all the cells are undifferentiatedinstead of just some of the lower layer.  In these patches all the cells are still confined within the basal lamina. Of those with patches, 20 to 30% will over the next several years develop cervical carcinoma and thus brake the basal lamina and invade the underlying connective tissue.

 

FACTORS DETERMINING THE RATE OF EVOLUTION INTO CANCER: (1) reproduction rate; (2) mutation rate; (3) number of cells in population; (4) selective advantage of mutant cells. The mutation rate leading to cancer can be effected by(in more technical terms):  polymorphisms in genes encoding metabolic/detoxification enzymes, carcinongen-DNA adducts, mutational spectra in reporter genes.  Thus for example, varioatons in the response in the expression or form of the metabolic genes P450, glutathione S-tranferase (GTS) and N-acetyltransferase (NAT) genes, strongly influence individual biologic response to carcinogens in so far as permitting residue or surrogate proteins (known as DNA adducts) to bind to DNA. Cigarettes, for example increase through the presence of benzophenyl the mutation of P53, predominantly the G to T transversions.  Defective P53 is most commonly brought about by either adducts or transversions.  In 40 to 50% of lung, breast and colon cancer the P53 suppressor gene is mutated.

 

TUMOR INITIATOR: a mutagen; TUMOR PROMOTER: a substance which does not cause cancer, but rather after exposure to a mutagen will cause an increased rate of cancerthe best studied group being phorbol esters, which are artificial activators of protein kinase C which causes continued and thus undifferentiated cell growth.  The result of such growth to a tissue exposed to an initiator is the formation of many benign, wart-like tumors called PAPILLOMAS.  A typical papillomas contains 100,000 cells, and if not continued exposed to the promoter, then most will regress to normal cells. However, if a mutation occurs which in a cell permits continued growth it may progress to cancer.  The rate of cells in a papillomas progress towards cancer is about the same for the normal population.

There are two basic ways cancer arises, one that the stem cell fails to produce differentiated stem cells, or that it of undifferentiated daughter

 

ENVIRONMENTAL FACTORS: based upon the comparison of low incidents in some countries, has lead to the estimate that 80 to 90% of cancers are prevent­able.  Some groups which avoid key hazards, such as the Mormons, have half the rate of the general population.

 

Besides the translocation cause of myelogenous leukemia, there comes ev­idence from the womans X-chromosome of other cancers caused by a gross error in the replication of a strand of DNA. 

 

Cancers which to date have been effective treated by chemotherapy frequently are one which have some marker which promotes selective destruction, such as for testicular cancer and for Hodgkins lymphoma.

 

Among the mutation necessary for invasive cancer is one that permits the crossing of the basal lamina, such as in the cervix. Such cells lose the cellcell adhesion molecule Ecadherin. Moreover they must carry on their surface typeIV collagenase, which helps them digest the lamina, and in addition they must have appropriate integrins to cat as laminin receptors which enable the cells to adhere to the lamina. Thus they first bind and then digest.

 

Cancer cells often display an adnormal variability in size and shape of their nuclei and in the number and structure of their chromosomes, this due to a failure of the mechanisms that control replication, repair, recombination, or segregation.  Such cells have a high rate of mutation, and therefore, under chemotherapy they possess the ability to develop in a few cells resistant to the drug treatment.  If such mutation occurs in the plasmamembranebound transport system, then resistance will be con­ferred to a number of drugs; a phenomenon called MULTIDRUG RESISTANCE.

 

Other mutation besides those which make the genes hyperactive, include those which have an inhibitory effect upon the genes; these are shut off.

 

Retroviruses insert genes into the DNA via the use of the enzyme REVERSE TRANSCRIPTASE, which thus promotes the synthesis of new viral DNA by the hosts DNA.  This process increases the rate of formation of tumors, because when the insertion occurs within 10,000 base pairs of a proto oncogene it will cause abnormal activation of that gene.  In some retro­viruses there is within the virus gnome a gene which promotes rapid cell proliferation; such cell of course will produce at a greater rate more viruses. But most simply involve the alteration of a proto-oncogene which is gene that controls cells proliferation), of which about 60 have thus far been discoveredan almost complete list.  Often the mutation effect the signal by a cell neighbor for the compromised cell to prolifer­ate, differentiate, or die. For example, 90% of the skin tumors evoked in mice by tumor initiator dimethylbenzanthracene (DMBA) have an A-to-T alter­ation at exactly the same site in the mutant ras gene.  So far only one effect has been found for DMBA. However, a single oncogene is not usually sufficient to turn a normal cell into a cancer cell.  In experiments in which in vivo an oncogene has been inserted, it was shown that further mutations must occur, with two such genes inserted the rate at which the transformation to cancer occurred was greatly enhanced.

An example of both random mutation and of genetic inheritance causing cancer is retinoblastoma, which afflicts about 1 in 20,000 children.  The Rb gene on chromosome 13 functions as a tumor suppressor.  In those with the hereditary form have throughout their body one good copy of the rb gene. The retinoblastoma cell do not have the rb gene. For the much rare cases of those without a genetic predisposition, there is required two mutations in a single retinal cell to elimination the Rb genes action. About 70% of the patients have the rare state of being heterozygostic for Rb.  It turns out that this gene is frequently missing in several common types of cancer: lung, breast, and bladder.  The Rb protein alternates between phosphorylated and an unphosphorylated state during every cell division.  In the unphosporlated state, Rb binds strongly to certain gene regulatory proteins to prevent them from acting in the nucleus to promote DNA replication.  Loss of the gene sets removes this restrain upon cell proliferation.  A similar pattern for p53 occurs.

 

Viruses are involved in about 15% of the cancers worldwide.  Some of these rather than being retro virusesdiscussed priorare either DNA or RNA viruses.  Such viruses most often function to promote cell division, rather than through the insertion of genes, which is the case with 5V40 virus.  Such activation permits the virus to utilize the cells protein for its replication; thereby, releasing thousands of viruses when the cell dies.  However, rarely the viral DNA fails to replicate and instead becomes in­corporated into the hosts chromosome.  If one such cell has the virus code for activation, is itself activated, then a precancerous transformation has occurred.  This is likely the case where a retrovirus gene insertion has inactivated one of the cells safeguards: these DNA and RNA viruses insert a gene not found in the cells gnome.  The 5V40 virus produces through genes E6 and E7 proteins that bind to a single large dualpurpose protein called large T antigen, which function to suppresses tumors while the other virus gene suppresses the protein of the gene PS³, also a tumor suppressor.

 

HUMAN CANCER HERETITARY SYNDROMES, of which more than 20 are known, account collectively for about 1% of cancer patients.  An individual who carries a mutant allele of an inherited cancer gene has a variable risk of cancer that is influenced by the particular mutation, other cellular genes, and also dietary, lifestyle, and environmental factors.  These individuals carry a particular germline mutation in every cell of their body.  Most commonly the protein encoded by the inherited cancer genes affect proliferation, differentiation, apoptosis, and maintenance of genomic integrity.  These proteins function as transmembrane receptors (MET, PTCH, RET), cytoplasmic regulatory or structural proteins (NF1, PTEN APC, NF2), transcription factors, or regulators of transcription (p53, WT1, RB1, VHL) cell cycle factors (CDK4 AND p16), or DNA damage repair pathway proteins (MSH2, MLH1, PMS2, ATM, BRCA1, BRCA2, FACC, FACA, XPA, XPB, XPD, BLM). 

 

 

To complicate the treatment, an assortment of mutations give rise to cancer, thus making each cancer unique.  For example some of the genetic abnormalities detected in colorectal cancer cells: Dras, chromosome 12, 50% neu, chromosome 17 2%, myc, chromosome 8, 2%; myc, chromosome 8, 2%; APC, chromosome 5, +70%; DCC, chromosome 18, +70%; p53, chromosome 17, +70%; HNPCC, chromosome 2, 15%. Such variation gives rises to different prognoses.

 

The p53 gene gives rise to a protein mainly in response to insult.  When normal cells are exposed to ultraviolet light or to gamma rays, the con­centration of the protein it expresses rises, and this blocks the cells from progressing into the S phase of mitosis, and also delays the G₁ phase or causes cell death by apoptosis. Cells lacking the p53 gene do not show such responses. These cells plug into DNA replication without pausing to repair the breaks and other DNA lesions caused by the damaging radiation.  A common consequence is that the chromosomes become fragmented and rejoined, creating a highly unstable karyotype.

 

The information above comes from my long and extensive reading of medical journals and textbooks, and from Science, 7 November 1997, Vol. 278, which ran a collection of articles under the heading of Frontiers in Cancer Research.