Cancer Cell Processes
In This Section:
Targeting Cancer Cell Processes
All cell processes—including growth, death, and differentiation—depend on the action of signaling molecules and pathways. A number of safeguards exist in normal cells to ensure that these processes are carried out correctly. But cancer cells employ mechanisms to bypass these safeguards so they can grow uncontrollably at the expense of normal cells and tissues. These mechanisms include increased signaling for cell growth, evasion of cell death, increased blood vessel formation, and invasion into surrounding tissues and metastasis.
In this section, we'll discuss how normal cells control their growth and explore some mechanisms used by cancer cells to bypass cellular safeguards. Examples of some therapies that target these sinister mechanisms will be presented.
In normal cells, growth, division, and differentiation are highly regulated processes. Some signaling molecules—called growth factors—promote cell division. Other signaling molecules cause cells to stop growing.
Many signaling molecules, including growth factors and growth inhibitors, bind to receptors on the surface of the cell. In many cases, these receptors must interact with one another, or dimerize, before they can become fully activated.
Once they are activated, receptors activate relay teams of proteins inside the cell—called signaling pathways. Activated signaling pathways carry messages from the receptor to the inside of the cell and sometimes all the way to the DNA in the nucleus.
Activation of these signaling pathways is often carried out by the transfer of chemicals, called phosphates, from one member of the relay team to the next. This process is known as phosphorylation. Receptors and other proteins that perform phosphorylation are called kinases.
The messages carried by the activated signaling pathways lead to the accumulation and activation of certain proteins that either promote or inhibit cell growth and division. The rate of cell growth and division depends on the balance of these two types of signals.
Unlike normal cells, cancer cells display uncontrolled growth control, so they can ignore signals to stop growing. Some cancer cells can make their own growth factors. These growth factors travel to the outside of the cell, where they interact with and activate the cancer cell's growth factor receptors.
Some cancer cells make more growth factor receptors than normal cells—this is called overexpression. Cancer cells with overexpressed growth receptors may be stimulated to grow when growth factors are present at levels that would be too low to stimulate growth of normal cells. This is because having more receptors available increases the chances that a growth factor will find its receptor.
Other cancer cells may have mutations in the genes that code for growth factor receptors. Some of these mutations result in the formation of dysfunctional receptors that remain in the "ON" position for growth even when no growth factor is present.
Cells can also bypass normal growth regulation by altering the way signals inside the cell operate. Increased levels of certain proteins in a pathway, or genetic mutations that alter these proteins, may cause the pathway to transmit growth signals on its own, with little or no regard for signals coming from nearby normal cells. Alternatively, other mutations may keep cells from receiving or transmitting signals that tell them to stop growing.
Targeted therapies can be designed to interfere with the renegade growth factor signaling of cancer cells. The goal is to block any part of a dysregulated growth signaling pathway from communicating with the other elements of the pathway.
For example, drugs that bind to a cancer cell's growth factor receptors can block the receptors from interacting with their growth factor or prevent them from dimerizing with other receptors.
Agents can also keep receptors in the "OFF" position or prevent them from transmitting a phosphorylation signal along the growth pathways within the cell.
Another strategy is to target the proteins that sit in relay teams and carry signals within the cell. The goal is to prevent them from transmitting the signal.
Drug Resistance and Targeted Therapies
Drug resistance is a serious problem for all cancer therapy. For targeted therapies, knowing the pathway that has been hit successfully before resistance developed, often helps researchers develop alternative molecules to again disrupt the cancer cells.
For example, resistance to the targeted drug Gleevec® (imatinib) is linked to mutations within the kinase domain of a protein called Bcr-abl. No novel pathways are involved. Using this knowledge, scientists have developed small molecule inhibitors that target this location. Dasatinib, also called Sprycel, developed by Bristol-Myers Squibb is a multi-targeted kinase inhibitor with higher affinity for the Bcr-abl kinase than imatinib. When patients who developed resistance to imatinib were given dasatinib, 93 percent of them again showed a response. Also, Novartis has developed a small-molecule kinase inhibitor called Tasigna (nilotinib) that can be given when a patient develops resistance to imatinib.
Example: Herceptin® (trastuzumab)
One example of a therapy designed to target a cell surface receptor is Herceptin® (trastuzumab). Herceptin® (trastuzumab) is a monoclonal antibody that interacts with a growth factor receptor called HER2. An excessive number of HER2 receptors are found in approximately 20% of breast cancers—and these cancers tend to be among the most aggressive types.
HER2 interacts—or dimerizes—with other receptors on the cell surface, activating signaling pathways that cause the cell to proliferate. One of the ways that Herceptin® (trastuzumab) works is by binding with HER2 and preventing it from interacting with other receptors on the cell surface. This keeps the receptor from activating the pathways that promote growth and division of breast cancer cells.
Herceptin® (trastuzumab) may also interfere with cancer cell growth by activating an immune response.
Herceptin® (trastuzumab) was initially approved by the FDA for the treatment of patients with HER-2 overexpressing metastatic breast tumors who had already received chemotherapy or who had not yet received chemotherapy and would be given Paclitaxel® along with Herceptin® (trastuzumab). More recently, Herceptin® (trastuzumab) has been approved for use as an adjuvant therapy in combination with doxorubicin, cyclophosphamide, and Paclitaxel® in women with earlier-stage HER2-positive disease. This approval was based on clinical trials that showed that women treated with this regimen had prolonged disease-free survival compared with women who received chemotherapy alone.
Example: Gleevec® (imatinib)
Gleevec® (imatinib) is a small molecule that blocks the signaling activity of certain proteins inside a cell. Proteins bound by Gleevec® (imatinib) cannot function in their relay team. They can no longer transmit phosphorylation signals along the pathways that lead to cell growth and division. Gleevec® (imatinib) can inhibit several different proteins, including two proteins involved in growth signaling.
Gleevec® (imatinib) was first developed for use in patients with chronic myelogenous leukemia, or CML. Gleevec® (imatinib) can inhibit several different proteins, including two proteins involved in growth signaling called abl and c-kit. Patients with CML have a mutant form of the abl protein known as Bcr-abl. Bcr-abl is stuck in the "ON" position and fuels cancer cell growth by phosphorylating other signaling pathway members. Gleevec® (imatinib) improves the chances of survival of CML patients. Gleevec® (imatinib) is also approved by the FDA for the treatment of unresectable or metastatic gastrointestinal stromal tumors that express a gene which makes another good Gleevec® (imatinib) target, the c-kit protein.
Normal Cell Death
We have shown that growth pathways and growth inhibition pathways regulate cell growth. Now we will look at another way normal cells control their growth. They use a process called apoptosis.
In adults, the number of body cells is kept relatively constant. Stressed, diseased, malfunctioning, or irreversibly damaged cells, as well as cells that need to be removed routinely as part of normal growth and development, are all removed by apoptosis, also called programmed cell death or cell suicide. Billions of adult cells die each day by apoptosis. These cells are then replaced by new, healthy cells. Within every cell there are signaling pathways that favor cell survival and others that favor apoptosis. The decision to undergo apoptosis depends on the balance of pro-apoptotic and pro-survival signaling pathways.
Signals that trigger apoptosis can come from outside or within the cell.
When the signal comes from the outside, a molecule released from a nearby cell binds to a surface receptor. This binding initiates pro-death signaling pathways within the cell. One signaling molecule, called TRAIL (TNF-related apoptosis-inducing ligand) can cause apoptosis when it binds to either Death Receptor 4 or Death Receptor 5.
Apoptosis can also be initiated from within a cell. Cells have a number of internal surveillance proteins that are constantly looking for signs of trouble, such as the presence of damaged DNA that cannot be repaired. If a serious problem is detected, pro-death signaling pathways are activated to begin the process of cell suicide.
Cells supervise their own self-destruction through a controlled series of steps. The process is highly regulated in order to minimize inflammation and harm to nearby cells.
The apoptotic cell shrinks and rounds itself up. Next, it condenses its DNA and cuts it into fragments. The cell eventually breaks into small vesicles that can be easily engulfed by immune cells called macrophages.
Cancer Cells Evade Cell Death
Normally, cells that begin to divide at the wrong time or with damaged DNA will undergo apoptosis. Cancer cells, however, develop a number of strategies to evade apoptosis. The ability to do this is critical to a cancer cell's survival. Avoiding apoptosis can also help cancer cells resist some therapies, such as radiation and conventional chemotherapy that work by inflicting enough cellular damage to prompt a call for apoptosis.
Cancer cells also often avoid apoptosis by altering the surveillance proteins that normally detect problems or induce apoptosis. Proteins that are responsible for these jobs can be rendered ineffective through mutation or by simply being produced at lower levels.
Some cancer cells evade apoptosis by overproducing anti-apoptotic proteins or creating mutant proteins that are better at blocking pro-apoptotic signals. For example, some cancer cells evade apoptosis by expressing high levels of the anti-apoptotic protein Bcl-2.
Targeted Therapies Promote Cell Death
The goal of therapies that target apoptosis is to tip the balance toward cell death for cancer cells.
Targeted therapies can be used in two different ways to promote apoptosis:
- Some therapies activate pro-apoptotic pathways, directly leading to cell death.
- Other therapies attempt to counter the overactive anti-death proteins present in cancer cells.
Although these therapies may cause cell death on their own, they are often used to prime cancer cells to be more responsive to other treatments, such as chemotherapy.
Example: HGS-ETR1 and HGS-ETR2
HGS-ETR1 (mapatumumab) and HGS-ETR2 (lexatumumab) are examples of apoptosis-inducing therapies. Both drugs are monoclonal antibodies. One binds to Death Receptor 4 and the other binds to Death Receptor 5.
To the receptors, the drugs look just like the signaling molecule TRAIL. So, the antibodies activate the pro-death signaling pathways that TRAIL usually triggers.
Death Receptors 4 and 5 tend to be more highly expressed in cancer cells than in normal cells. This is important because drugs that target these death receptors may be able to induce apoptosis in cancer cells while only minimally affecting normal cells.
HGS-ETR1 & HGS-ETR2
HGS-ETR1 (mapatumumab) is currently being tested in clinical trials for the treatment of adults with relapsed or refractory multiple myeloma. Clinical trials are also evaluating HGS-ETR2 (lexatumumab) in pediatric patients with relapsed or refractory lymphoma or solid tumors, including Ewing sarcoma.
Normal Blood Vessel Formation
The creation of new blood vessels—a highly regulated process called angiogenesis—primarily takes place during early development, when the circulatory system is being formed. In adults, however, angiogenesis normally occurs only to facilitate wound healing or to support various aspects of female reproduction and pregnancy.
On a cellular level, the process of angiogenesis involves a cry for help from a nearby cell that is in need of nutrients or oxygen. The cell releases proteins that specifically seek out and bind to receptors on the surface of endothelial cells that make up blood vessels.
In response to this signal, endothelial cells secrete a special class of proteins called matrix metalloproteinases, or MMPs.
These MMPs clear a path that allows endothelial cells to migrate in the direction of the cell in need and form new blood vessels.
Cancer Cells and Blood Vessel Formation
Once a tumor reaches a certain size (1 cubic millimeter), it requires a blood supply to continue growing. So, tumor cells must find a way to attract new blood vessels. Many tumors release high levels of proteins, such as vascular endothelial growth factor, or VEGF, that bind to and activate the endothelial cells of nearby existing blood vessels.
Tumors can also produce MMPs to help carve pathways for the new blood vessels to follow.
Targeted Therapies Inhibit Blood Vessels
Because angiogenesis is essential for tumors to grow beyond a certain size, blocking angiogenesis is an ideal strategy for cancer therapy. Agents can be developed to interfere with any one of the steps of new blood vessel growth.
Drugs can be designed to bind to either the proteins released from the tumor, or receptors on the endothelial cell surface, to prevent the two from interacting. Efforts can also be made to interfere with the activity of MMPs and prevent them from clearing the road for blood vessel expansion.
The first monoclonal-antibody inhibitor of angiogenesis, Avastin® (bevacizumab), was approved by the Food and Drug Administration (FDA) in 2004. This approval was based on the survival benefit observed in a randomized Phase III trial of first-line treatment of metastatic colorectal cancer. In that trial, bevacizumab, a humanized monoclonal antibody directed against VEGF, was combined with conventional chemotherapy. Bevacizumab therapy also increased overall survival in the first-line treatment of advanced non-small-cell lung cancer when used in combination with standard chemotherapy. In addition to being approved by the FDA for use in patients with metastatic colorectal cancer, bevacizumab is approved for patients with unresectable or recurrent non-squamous non-small cell lung carcinoma. It is also being tested in clinical trials for the treatment of a number of other tumor types.
Two other antiangiogenic drugs, Nexavar® (sorafenib) and Sutent® (sunitinib), have also been approved by the FDA; these are oral small-molecule receptor tyrosine kinase inhibitors. They target multiple receptor tyrosine kinases, including VEGF receptors and platelet-derived growth factor receptors. Sorafenib and sunitinib have been beneficial in the treatment of metastatic renal-cell cancer.
Example: Avastin® (bevacizumab)
When a patient is given Avastin® (bevacizumab), this monoclonal antibody binds to VEGF and keeps it away from receptors on the surface of endothelial cells. Existing blood vessels no longer receive a signal for increased blood flow, so new blood vessels are not formed. This prevents the tumor from continuing to grow.
Example: Nexavar® (sorafenib)
Nexavar® is a small molecule that inhibits multiple kinases—the proteins involved in growth signaling that were described earlier. These kinases include some cell surface receptors as well as enzymes located within the cell.
In addition to blocking the signaling pathways for growth, disrupting kinase signaling also interferes with the tumor's recruitment of new blood vessels.
Nexavar® (sorafenib) is FDA-approved for treatment of advanced renal cell cancer. It is being tested in clinical trials with Avastin® (bevacizumab) to treat advanced melanoma, ovarian cancer, and other advanced-stage solid tumors. Because the kinases targeted by Nexavar® (sorafenib) are also important to some normal cells, therapies like Nexavar® (sorafenib) may affect some normal cells as well.
- A protein that is part of a growth signaling pathway inside the cell is mutated, causing it to become continually active and resulting in the formation of a tumor. What type of targeted therapy might be effective?
- Monoclonal antibody that prevents growth factors from interacting with the receptor
- Monoclonal antibody that holds the growth factor receptor in the "OFF" position
- Small molecule that selectively binds to the mutated protein
- Monoclonal antibody that selectively binds to the mutated protein
- How do cancer cells evade apoptosis?
- Reduce the activity of proteins that detect DNA damage
- Mutation of proteins that induce apoptosis
- Increase the activity of proteins that prevent apoptosis
- All of the above
- Angiogenesis inhibitors will prevent existing blood vessels from delivering oxygen and nutrients to normal cells.
- Correct answer to Question 1: c
- Monoclonal antibody that prevents growth factors from interacting with the receptor - There is a better answer. Since the mutated protein is inside the cell and downstream of the growth factor receptor, preventing the growth factor receptor from being activated is unlikely to overcome the activity of the mutated protein.
- Monoclonal antibody that holds the growth factor receptor in the "OFF" position - There is a better answer. Since the mutated protein is inside the cell and downstream of the growth factor receptor, keeping the growth factor receptor inactive is unlikely to have an effect on the mutated protein.
- Small molecule that selectively binds to the mutated protein - Correct answer. A small molecule would be able to enter the cell and interfere with the activity of the mutated protein.
- Monoclonal antibody that selectively binds to the mutated protein - There is a better answer. A monoclonal antibody cannot easily enter cells so it would not be able to interfere with the activity of the mutated protein.
- Go to Question 2.
Correct answer to Question 2: d
- Reduce the activity of proteins that detect DNA damage - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- Mutation of proteins that induce apoptosis - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- Increase the activity of proteins that prevent apoptosis - There is a better answer. This is one way that cancer cells can evade apoptosis, but not the only way.
- All of the above - Correct answer. Cancer cells can use a variety of mechanisms to evade apoptosis, such as reducing the activity of proteins that detect problems within the cell, mutation of proteins that induce apoptosis or reduction of their activity, and increasing the activity of proteins that prevent apoptosis.
- Go to Question 3.
Correct answer to Question 3: b
- True - There is a better answer. Angiogenesis inhibitors do not affect established blood vessels, such as those that deliver oxygen and nutrients to normal adult cells. Angiogenesis only occurs in a few situations in adults.
- False - Correct answer. Angiogenesis inhibitors affect the formation of new blood vessels, but they do not interfere with the already existing blood vessels that deliver oxygen and nutrients to normal adult cells.