EFB325 Cell Physiology

Cancer: Disrupted regulation of growth

Cancer is a disease that approximately 40% of men and 30% of women in the U.S. will acquire in their lifetimes. Slightly more than 20% of Americans die from cancer. It is estimated that cancer treatment costs approach $37 billion each year (in the U.S.). The U.S. government will spend approximately $4 billion dollars to support cancer research next year.

Besides the importance of cancer as a human disease, the study of cancer has lead us to learn a great deal about the normal systems of growth regulation in animal cells.

What controls the normal growth of human cells?

When human cells are grown in tissue culture (in a Petri dish), they . . .

• require growth factors-hormones that trigger cell division and differentiation (for example, epidermal growth factor or platelet-derived growth factor)
• need to be anchored to a surface to grow
• grow until they contact another cell, then stop; this way the cells grow as a single-celled layer of cells (contact is sensed by cell-cell adhesion proteins like integrins and cadherins)
• will only divide about 40-50 times, then they stop dividing and become senescent (the "cell age clock" is the telomeres, which get shorter each time the chromosomes are replicated)

Tissues normally grow and develop to a certain size, then that size is maintained by restricted cell division

• tissues are normally renewed/maintained by a special set of undifferentiated cells called stem cells, which can divide continuously
• otherwise, most differentiated somatic cells (non-gametes) do not divide

The regulation of whether a cell divides or not (its progression through the cell cycle) is a balance between two sets of genes: those that promote cell proliferation and those that restrict it

• genes that promote cell division and proliferation are called proto-oncogenes
• those that suppress cell proliferation are called tumor-suppressor genes

What is cancer and how does it progress in the body?

• cancer is an unregulated proliferation of mutant cells
• the cells acquire initial mutations that result in prolific growth, then accumulate more in the progression of the disease (usually 5 or more mutations accumulate)
• the cells lose their normal shape, size, and chromosome number
• then become invasive, moving to other tissues and multiplying there
• eventually disrupting the proper function of that organ or tissue

The progression of tumor growth

1) a mutation makes a particular cell more likely to proliferate=hyperplasia
2) when additional mutations accumulate, the cells lose their normal shape=dysplasia
3) continued abnormal localized growth produces in situ cancer
4) when the tumors attract blood vessels to feed the tumor=angiogenesis
5) next, cells gain the ability to leave their tissue, enter blood vessels or lymph and travel through the body=malignancy
6) when cancer cells have invaded other tissues and form tumors there=metastases

Cancer results from the progressive accumulation of mutations that hyperactivate proto-oncogenes (they mutate to become oncogenes) and mutations that inactivate tumor-suppressor genes

Proto-oncogenes mutate to form oncogenes that stimulate the growth pathways

• mutations in growth factor receptor proteins cause them to be active even in the absence of the growth factor
• mutant cells overproduce growth factor, which stimulates their own cell division
• mutations in the Ras protein make it always active (does not need to be activated by the receptor) [20-30% of cancers have mutations in Ras]
• mutations in the kinases that are activated by Ras cause them to be always active, causing overexpression of genes involved in cell proliferation
• mutations in cyclins or Cdk cause them to always stimulate progress through the cell cycle
• mutations that turn on telomerase allow "immortal" cell division [nearly all cancers produce telomerase while normal cells don't]
• mutations in DNA repair enzymes allow accelerated accumulation of mutations

Mutations in tumor-suppressor genes remove the inhibitions on cell growth

• mutations in Rb remove controls on the cell cycle [40% of cancers have mutations in Rb]
• mutations in p53 remove the cell's "watchdog" allowing mutant cells to divide - also removes the signal for cells to "commit suicide" when damaged [50% of cancers have mutations in p53]
• mutations in cadherins or integrins remove the requirement for attachment and the inhibition by cell-cell contact (cancer cells grow on top of each other in culture, allows tumor cells to penetrate other tissues)

What causes cancer?

• things that cause mutations (ionizing radiation, UV light, mutagenic chemicals)
• certain viruses
• inherited genes can predispose an individual to cancer (cancer gets a head start)

What can you do to reduce your risk of cancer?

• smoking causes cancer (so stop smoking)=estimated that 150,000 cancer deaths due to smoking in U.S. annually
• diets high in saturated fat and low in fruits and vegetables, especially with lack of exercise, obesity, alcohol increase risk of cancer
• some sexually transmitted viruses can cause cancer

How is knowledge of the mechanisms of cancer development leading to novel methods of cancer detection and treatment?

• detection of mutations in some of the particular genes mentioned above (p53, Rb, Ras) before the tumor metastasizes Early detection and localization of tumors before they metastasize is crucial for most successful treatment
• DNA screens for inherited predisposition to certain types of cancer
• treatment by inject antibodies that will bind to cancer cells and kill them
• drugs targeted to inhibit proteins that are out-of-control "on" like Ras or growth factor receptors
• drugs to inhibit telomerase, which causes cells to be immortal
• gene therapy= treatments that add a "normal" copy of a gene to cancer cells to replace mutated tumor suppressor genes or DNA repair enzymes
• modify viruses to grow only in cancer cells, then kill them

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