Cancer and Oncogenes

Cancer is a diverse group of diseases with one common characteristic: unchecked cellular replication.  Via several potential mechanisms, cancer cells are able to avoid all of the checkpoints involved in cell growth and division, thus enabling them to divide more frequently or indefinitely.  Many events can lead to the development of a cancer cell, including inheritance of mutated DNA or the activity of a carcinogen, or a chemical agent that leads to the development of cancer.

Gene expression is often deregulated in cancer cells such that some genes are overexpressed, while others are underexpressed.  Genes that can be mutated to lead to an upregulation of activity and lead to the development of a cancer cell are termed proto-oncogenes.  When these proto-oncogenes are actually mutated, they are considered oncogenes.

An oncogene is often a gene involved in regulating cell division and drive the cell cycle.  When they are overexpressed, such as during cancer, they can push the cell to divide more frequently and, with further mutations, transform the cell such that it divides without restriction.

Oncogenes were first discovered in viruses, specifically in Rous Sarcoma Virus (RSV), a retrovirus that encodes a homologue to cellular src kinase (the viral form called v-src).  Tumors in birds caused by RSV are the result of v-src causing unregulated cellular proliferation.  Large amounts of research into this area has identified cellular src kinase as a proto-oncogene that, when mutated to become constitutively active, becomes an oncogene and can drive cancer development.  Interestingly, viruses have highlighted a number of cellular oncogenes and pathways that are improperly regulated in cancer.  Over 20 viral oncogenes have been identified to date.

Cellular proto-oncogenes (the genes before they become oncogenes) can promote cellular proliferation and the development of cancer in several ways.  One of these ways is to be overexpressed and function when the gene product really shouldn't function.  This is the case with proteins such as myc and growth factor receptors.  With overexpression of these proteins, there is the potential for amplified signaling through these pathways that can push the cell to divide more than it normally does, leading to the development of cancer.  An additional mechanism whereby a proto-oncogene can become an oncogene is via mutation that leads to improper regulation, such as constitutive activity.  A classical example of this type of phenomenon is via Ras, which when mutated is constitutively active and cannot hydrolyze an attached GTP to inactivate.  Thus, Ras remains active and cannot be "turned off."  This constant activity of Ras results in  signal transduction to the nucleus of the cell and pushes the cell to divide through transcription of several genes involved in cell division.

Oncogenesis Part 1: General Introduction

Oncogenesis

Benign tumors consist of cells that closely resemble and may function as normal cells that do not form malignant tumors.  They remain localized and stay small, with a fibrous capsule bounding the tumor.  However, if the benign tumor begins to interfere with normal function of other cells, such as via secretion of substances (such as hormones), the tumor can become a problem. 

In the case of malignant tumors, the cells express some characteristic proteins, but they grow out of control and more rapidly.  Malignant tumors also invade other tissues and can grow in sites vastly different from where they originated in a process terms metastasis.  The most diagnostic characteristic of a malignant tumor is its ability to invade other tissues.  These cells can break contacts with other cells and pass through the basal lamina to reach different areas of the body.  To facilitate this, cancer cells can secrete proteases such as plasminogen activator.  Plasminogen activator results in the formation of active plasmin from plasminogen, which helps to break down the basal lamina.  When the cell has passed the basal lamina, it can enter the blood stream and move to nearly any site in the body.  Roughly on in a million cells will be able to colonize another tissue, a hallmark of malignant tumors. 

Malignant tumor cells also have a high nucleus-to-cytoplasm ratio, with prominent nucleoli and many mitochondria, indicating high metabolic rates and significant growth.  Additionally, these cells appear to be de-differentiated, with few specialized structures that we would normally see in a cell.  Based on the cell’s gene expression and morphology, one usually is able to identify the source of a malignant tumor because it does retain some of the characteristics of its cellular origin. 

Carcinomas are cancers that have derived from the endoderm or ectoderm, while sarcomes are derived from the mesoderm.  Approximately 200 different cancer types have been identified, and there are approximately 300 different cell types in the body, meaning that cancer can arise from nearly any cell.

When a benign tumor grows, it is largely limited in size due to the inability for the tumor to acquire nutrients.  These tumors rely on diffusion to fuel the tumor cells.  In contrast, malignant tumors grow large, and in order to provide the nutrients necessary for growth of the tumor, they must recruit the formation of blood vessels in a process termed angiogenesis.  When a malignant tumor reaches a size over one million cells (or about 2 mm in diameter), it will induce the formation of blood vessels to provide nutrients to more cells.  Factors such as bFGF, TGFα, and VEGF are secreted by many tumors to facilitate angiogenesis.  Malignant tumor cells can also secrete factors that affect nearby cells to promote angiogenesis.  The larger the primary tumor, the higher the risk of metastasis is. 

Steps in metastasis of epithelial cells

1. Upregulated cell growth in epithelium
2. Invasion of the basal lamina via an invadopodium
3. Entry into blood vessels; traveling through  the bloodstream
4. Adherence to blood vessel wall
5. Escape from blood vessel
6. Colonizing of foreign tissue

The invadopodium consists of all the factors one would expect in an appendage to the cell: actin regulators such as WASP and Arp2/3; signaling molecules such as Cdc42; adhesion molecules such as integrins; and membrane remodeling complexes.

Tumors can be viewed as complex tissues in which the cell types have mutated to make a new phenotype (neoplastic phenotype).  It is important to note that these tumors are not growing in isolation, and they require interactions with non-cancer cells to grow as well.  The newest cancer therapies have begun to target these interactions in hopes of stemming tumor growth.

Genetically, cancer cells are messed up.  Therefore, one mutation in a cell does not cause cancer:  there are many different genes and factors that must become differently active for cancer to evolve.  Many different types of cancers evolve over time, meaning that the longer one lives, the higher the chance of cancer developing.  The multi-hit model indicates that successive mutations in a cell, each of which confers a growth advantage, will promote cancer development. 

For cancer cells to survive and proliferate unchecked, there are a number of functional capabilities that it must alter:

1. Self-sufficiency in growth signals
2. Insensitivity to anti-growth signals
3. Tissue invasion (metastasis)
4. Limitless replication
5. Angiogenesis
6. Evasion of apoptosis

There are a number of ways for a cancer cell to alter these pathways, and the order in which these capabilities emerge is different based on cell type and cancer type.  Additionally, there are a number of ways that cells are able to alter their function.  For example, the mutation of pRb can allow the cell to become immortalized and resist growth inhibition.  Mutations in p53 confer apoptosis evasion, resistance to growth invasion, and immortalization.  hTERT, which is the catalytic domain of telomerase, mutations will allow unlimited replication.  Mutations in Ras will allow for apoptotic evasion, growth in the absence of signals, angiogenesis, and metastasis.  Finally, mutations in PP2A (protein phosphatase 2A) affects signaling pathways that can affect a number of these alterations in cellular function.