Dr. Ali K. Shaaeli MBChB, FACS

2016

To understand the biological nature of cancer

To understand the principles of cancer prevention and early detection

To know the principles of cancer etiology and the major causative factors

To know The likely shape of future developments in cancer management

To know The multidisciplinary management of cancer

To know The principles of palliative care

The name ‘cancer’ comes from the Greek and Latin words for a crab, and refers to the claw-like blood vessels extending over the surface of an advanced breast cancer.

Cancer cells are psychopaths. They have no respect for the rights of other cells. Their proliferation is uncontrolled; their ability to spread is unbounded. Their inexorable, relentless progress destroys first the tissue and then the person.

1. Establish an autonomous lineage: a- resist signals that inhibit growth. b- acquire independence from signals stimulating growth

2. Obtain immortality 3. Evade apoptosis 4. Acquire angiogenic competence 5. Acquire the ability to invade 6. Acquire the ability to disseminate and implant 7. Evade detection/elimination 8. Genomic instability 9. Jettison excess baggage 10. Subvert communication to and from the

environment 11. Develop ability to change energy metabolism

This involves developing independence from the normal signals that control supply and demand.

Cancer cells escape from this normal system of checks and balances: they grow and proliferate in the absence of external stimuli regardless of signals telling them not to do so.

Oncogenes, an aberrant form of normal cellular genes, are a key factor in this process

According to the Hayflick hypothesis, normal cells are permitted to undergo only a finite number of divisions. For humans, this number is between 40 and 60.

Cancer cells can use the enzyme telomerase to rebuild the telomere at each cell division, so there is no telomeric shortening and the lineage will never die out. The cancer cell has achieved immortality.

Apoptosis is a form of programmed cell death which occurs as the direct result of internal cellular events instructing the cell to die

Cells that find themselves in the wrong place normally die by apoptosis

Cancer cells will be able to avoid apoptosis, which means that the wrong cells can be in the wrong places at the wrong times.

A mass of tumor cells cannot, in the absence of a blood supply, grow beyond a diameter of about 1 mm.

The ability of a tumor to form blood vessels is termed ‘angiogenic competence’ and is a key feature of malignant transformation.

Cancer cells have no respect for the structure of normal tissues. They acquire the ability to breach the basement membrane and thus gain direct access to blood and lymph vessels

Three mechanisms to facilitate invasion: (1) They cause a rise in the interstitial pressure within a tissue; (2) They secrete enzymes that dissolve extracellular matrix; and (3) They acquire motility.

Once cancer cells gain access to vascular and lymphovascular spaces, they have acquired the potential to use the body’s natural transport mechanisms

. They also need to acquire the ability to implant.

Cancer cells are simultaneously both ‘self’ and ‘not self’.

(‘self’), they are, in terms of their genetic make up, behavior and characteristics,

Foreign (‘not self’). As such, they ought to provoke an immune response and be eliminated and it is entirely possible that malignant transformation is a more frequent event than the emergence of clinical cancer.

The possible role of the immune system in eliminating nascent cancers Cancer cells, or at least those that give rise to clinical disease, appear to gain the ability to escape detection by the immune system.

This may be by suppressing the expression of tumor-associated antigens,

A cancer Cells are dividing without proper checks and balances.

Mutations, particularly those in tumor suppressor genes, may have the ability to encourage the development and persistence of further mutations.

This gives rise to the phenomenon of genomic instability – as it evolves, a cancer contains an increasing variety and number of genetic aberrations:

the greater the number of such abnormalities, the greater the chance of increasingly deviant behavior

Cancer cells are geared to excessive proliferation. They do not need to develop or retain those

specialized functions that make them good cellular citizens.

They can therefore afford to repress or permanently lose those genes that control such functions.

This may bring some short-term advantages. The longer-term disadvantage is that what is

today superfluous may, tomorrow, be essential. This can leave cancer cells vulnerable to external

stress and may, in part, explain why some cancer treatments work.

Providing false information is a classic military strategy.

Degrading the command and control systems of the enemy is an essential component of modern warfare. Cancer cells almost certainly use similar tactics in their battle for control over their host.

Given the complexity of communication between and within cells, this is not an easy statement to prove or disprove. Nor does it offer any easy targets for therapeutic manipulation.

Blood flow in tumors is often sporadic and unreliable. As a result, cancer cells may have to spend prolonged periods starved of oxygen – in a state of relative hypoxia.

Compared to the corresponding normal cells, some cancer cells may be better able to survive in hypoxic conditions.

This ability may enable tumors to grow and develop despite poor blood supply.

Cancer cells can alter their metabolism even when oxygen is abundant, they break down glucose but do not, as normal cells would do, send the resulting pyruvate to the mitochondria for conversion, in an oxygen-dependent process, to carbon dioxide. This is the phenomenon of aerobic glycolysis, and leads to the production of lactate.

In an act of symbiosis, lactate-producing cancer cells may provide lactate for adjacent cancer cells which are then able to use it, via the citric acid cycle, for energy production.

This cooperation is similar to that which occurs in skeletal muscle during exercise.

The interplay between nature and nurture

Both inheritance and environment are important determinants of cancer development. Although environmental factors have been implicated in more than 80 per cent of cases, this still leaves plenty of scope for the role of genetic inheritance: not just the 20 per cent of tumors for which there is no clear environmental contribution but also, as environment alone can rarely cause cancer, the genetic contribution to the 80 per cent of tumors to which environmental factors contribute.

Syndrome Gene Inh Associated Tumors

MEN type 2b

RET D Medullary carcinoma of the thyroid Phaeochromocytoma Mucosal neuromas Ganglioneuromas of the gut

Familial breast cancer

BRCA1, BRCA2 D Breast cancer Ovarian cancer Papillary serous carcinoma of the peritoneum Prostate cancer

Xeroderma pigmentosum

Deficient nucleotide excision repair (XPA, B, C)

R Skin sensitive to sunlight; early onset of cutaneous carcinomas (SCCs, BCCs)

Environmental/behavioral factor Associated tumors

Tobacco Lung cancer Head and neck cancer

Alcohol Head and neck cancer Oesophageal cancer Hepatoma

UV exposure Melanoma Non-melanoma skin cancer

Fungal and plant Aflatoxins toxins

Hepatoma

Obesity/lack of physical exercise

Breast Endometrium Kidney Colon Oesophagus

Management is more than treatment The traditional approach to cancer

concentrates on diagnosis and active treatment. This is a very limited view that, in terms of the public health, may not have served society well.

Cancer management can be considered as taking place along two axes:

1-One an axis of scale, from the individual to the world population; 2-The other based prevention to rehabilitation or palliative care

In 1998, Sir Richard Doll estimated that

30 per cent of cancer deaths were due to tobacco use and that up

to 50 per cent of cancer deaths were related to diet.

Screening involves the detection of disease in an asymptomatic population in order to improve outcomes by early diagnosis.

a successful screening program must achieve

early diagnosis, and that the disease in question has a better outcome when treated at an early stage.

Accurate diagnosis is the key to the successful management of Cancer.

Precise diagnosis is crucial to the choice of correct therapy

It is not sufficient simply to know what a cancer is;

it is imperative to know its site and extent.

Staging is the process whereby the extent of

disease is mapped out

As the management of cancer becomes more complex,

It becomes impossible for any individual clinician to have the intellectual and technical competence that is necessary to manage all the patients presenting with a particular type of tumors

Diagnosis and staging

Removal of primary disease

Removal of metastatic disease

Palliation

Within a month of their discovery in 1895, x-rays were being used to treat cancer

it was assumed that the biological effects of radiation resulted from radiation induced damage to the DNA of dividing cells.

Selective toxicity is the fundamental principle underlying the use of chemotherapy in clinical practice.

The importance of the principle is further emphasized by the fact that, by itself, chemotherapy is rarely sufficient to cure cancer