exam 4- Cancer

Most cancers are in three main groups

*Carcinomas—*malignancies of epithelial cells (about 90% of human cancers). *Sarcomas—*solid tumors of connective tissue such as muscle, bone, cartilage, and fibrous tissue (rare in humans). *Leukemias* and *lymphomas* arise from the blood-forming cells and immune system cells, respectively. Tumors are further classified according to tissue of origin and type of cell involved.

Tumor VirusesSmall DNA tumor viruses

*Papillomaviruses* :About 100 different types infect epithelial cells. Some cause benign tumors (e.g., warts); others cause malignant carcinomas, particularly cervical and other anogenital cancers.

Cancer cells secrete growth factors that promote formation of new blood vessels in a process called

*angiogenesis*

Many cancer cells fail to undergo *programmed cell death* or

*apoptosis* and have longer life spans than normal cells

*any oncogenes encode components of signaling pathways that stimulate*

*cell proliferation*

Study of tumor induction was advanced by development of in vitro assays to detect

*cell transformation*— conversion of normal cells to tumor cells

*studies of viral oncogenes led to identification of cellular oncogenes involved in development of*

*non-virus-induced cancers*

*it is estimated that smoking is responsible for nearly*

*one-third of all cancer deaths*

*Oncogenes such as raf are fusion proteins. In such cases, regulatory regions that would normally control function are replaced, generating*

*proteins that are constitutively active and cause cell transformation

*normal cells must contain genes that are closely related to the*

*retroviral oncogenes*

Because RSV causes sarcomas, the oncogene was called

*src*

Colon carcinoma is an example of

*tumor progression* -Proliferation of colon epithelial cells gives rise to a small benign neoplasm (an *adenoma* or *polyp*) -Clonal selection leads to growth of adenomas of increasing size and proliferative potential

Descendents of these cells dominate the tumor via -*clonal selection,*-

-Descendents of these cells dominate the tumor via clonal selection,-

At the cellular level, development of cancer is a multistep process

-Mutations occur-, followed by -selection/survival- of cells with progressively increasing capacity for -proliferation, survival, invasion, and metastasis-

The loss of growth control exhibited by cancer cells is the net result of accumulated abnormalities in multiple cell regulatory systems

-more than 100 types of cancer -It is reflected in several aspects of cell behavior that distinguish cancer cells from their normal counterparts

Cancer results from a breakdown of the regulatory mechanisms that govern normal cell behavior, such as responding to normal cell signaling and growth cues

Cancer cells grow and divide in an uncontrolled manner, spreading throughout the body (via metastasis) and interfering with the function of normal tissues.

Cancer cells secrete proteases that digest extracellular matrix components, allowing them to invade adjacent normal tissues

Example: Proteases that digest the extracellular matrix protein called collagen can allow carcinomas to penetrate the basal lamina and invade underlying connective tissue.

The four most common cancers are prostate, breast, lung, and colon/rectum

Lung cancer, by far the most lethal, is responsible for nearly 30% of all cancer deaths.

Cancer cells are less regulated by cell-cell and cell-matrix interactions

Most cancer cells are less adhesive than normal cells, due to reduced expression of cell surface adhesion molecules. Reduced adhesion molecules make cancer cells less restrained by interactions with other cells and the matrix, contributing to their ability to invade and metastasize

Tumor cells are often able to survive in the absence of growth factors required by normal cells

Normal cells also undergo apoptosis following DNA damage, while many cancer cells do not. This contributes to resistance of cancer cells to irradiation and many chemotherapeutic drugs, which act by damaging DNA

Cancer cells have *characteristic properties* that distinguish them from normal cells and contribute to malignancy

Reduced cell adhesion molecules (don't sense neighbors) Reduced dependence on growth factors Uncontrolled proliferation Secretion of proteases Promotion of *angiogenesis* (generate blood vessels for blood supply) Abnormal differentiation (de-differentiation) Failure to undergo apoptosis (programmed cell death) Capacity for unlimited replication

Cell proliferation is also stimulated in other ways

Hormones, particularly estrogens, are tumor promoters in some human cancers. Exposure to excess estrogen significantly increases the likelihood that a woman will develop uterine cancer. Asbestos is a tumor-promoting carcinogen The bacterium Heliobacter pylori causes stomach cancer. *DNA tumor viruses* cause cancer, including liver cancer and cervical carcinoma.

Clonal selection continues throughout tumor development, so different clusters of cells within tumors continuously become

more rapid-growing and increasingly malignant

*tumor initiation:*

mutation leads to abnormal proliferation of a single cell, which grows into a clonal population of tumor cells

The gene product encoded by v-src (viral src) causes transformation

of the host cell. The phenotype was observed but src function was not yet known

*benign tumors*

remain confined to the original location, neither invading surrounding normal tissue nor spreading to distant body sites

*Carcinogens*

substance that causes cancer

*proto-oncogenes*

the normal genes in normal cells, that respond to normal cellular regulation pathways. They often encode proteins in the signaling pathways that control normal cell proliferation (e.g., src, ras, raf )

*malignant tumors

can invade surrounding normal tissue and spread throughout the body via the circulatory or lymphatic systems *(metastasis)* -only ones referred to as cancers

*Oncogenes* are specific genes that can induce

cell transformation

Therefore, one of the difficulties in understanding tumors is that they can be

compromised pf multiple clones with various characteristics

in contrast, tumor cells continue moving after

contact, migrating over adjacent cells, growing in disordered, multilayered patterns

This was demonstrated in 1976 by Varmus and Bishop, who showed that a cDNA probe for srchybridized to closely-related sequences in DNA of normal chicken cells.src-related sequences were also found in normal DNAs in many vertebrates and appeared to be highly conserved in evolution.

first example of a *proto-oncogene*

*tumor progression*

additional mutations occur within cells of the tumor population, leading to multiple clones within a tumor; some clones eventually metastasize.

*tumor*

any abnormal proliferation of cells

*Malignant carcinomas*

arise from the benign adenomas; tumor cells invade the underlying connective tissue

in culture, normal cells display *density-dependent inhibition (also called contact inhibition):*

They proliferate until reaching a finite cell density, determined partly by availability of growth factors. They then cease proliferating and are arrested in the G0 stage of the cell cycle

Most cancer cells don't differentiate normally, and they show abnormal proliferation

While normal cells cease cell division once fully differentiated into a specific cell type, cancer cells behave more like undifferentiated cells (highly proliferative, migratory).Example: Leukemias

Normal fibroblasts show contact inhibition:

They migrate across a culture dish until making contact with a neighboring cell. Normal cells adhere to each other, forming an orderly array.

Radiation and many chemical carcinogens damage DNA and induce mutations

Solar ultraviolet radiation—the major cause of skin cancer. Aflatoxin—produced by some molds that contaminate peanuts and stored grains. Chemicals in tobacco smoke include benzo(α)pyrene, dimethylnitrosamine, and nickel compounds.

*Hepatitis B* and *C viruses* are the main causes of liver cancer

The viruses infect liver cells and can lead to long-term chronic infections, associated with a high risk of cancer. The molecular mechanisms by which they cause cancer are not well understood. A viral protein may interact with p53 protein. The chronic tissue damage and inflammation in hepatitis B results in continual proliferation of liver cells, and may contribute to tumor development

When a tumor reaches about a million cells, new blood vessels are needed to supply enough oxygen and nutrients for tumor survival*

These new capillaries are easily penetrated by tumor cells, contributing to *metastasis* (spread of the tumor cells to other organs, at a site distant from the primary tumor)

In contrast, cancer cells (bottom of next slide) are not restricted by growth factor availability or cell-cell contact.

They don't respond to the signals that cause normal cells to cease proliferation, but grow to high densities in culture.

*Tumor viruses* can directly cause cancer in humans or animals

They have played a critical role in cancer research by serving as models for cell transformation and by allowing identification of viral genes responsible for cancer induction.

Retroviral oncogenes differ from proto-oncogenes

Transcription in viral oncogenes is controlled by viral promoters and enhancers. Viral oncogenes are usually expressed at much higher levels than proto-oncogenes .Oncogenes often encode proteins that differ in structure and function from normal proteins. Many oncogenes differ from the proto-oncogenes by point mutations, resulting in single amino acid substitutions, which can also lead to unregulated activity

Tumor cells have high frequency of mutations and chromosome abnormalities

Tumor cells have high frequency of mutations and chromosome abnormalities