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Colon cancer, commonly grouped together with colorectal cancer, is cancer of the large intestine – the final portion of the digestive tract. It is the most common of all gastrointestinal cancers.
Colon cancer usually starts from a small growth called a polyp. Polyps are very common, but most polyps do NOT become cancers. Polyps can be of various types, some of which are more likely to develop into malignant tumors than others.
Early-stage colon cancer generally produces NO symptoms. Advanced-stage symptoms VARY depending on the location of the tumor, and may include: changes in bowel habits that PERSIST for weeks; blood in stool; abdominal pain and discomfort; constant feeling that the bowel doesn’t empty completely; fatigue; and unexplained weight loss.
Early detection is the key to prevent colon cancer. Because a pre-cancerous polyp usually takes YEARS to develop into a malignant tumor, colon cancer can be effectively prevented with regular screening. There are 2 major types of screening tests:
– Stool-based tests: stool samples are examined for signs of cancer, such as blood and mutated DNA. These tests are NON-invasive but LESS effective and need to be done more often.
– Visual screening, such as colonoscopy, is more reliable and can be done every 5 or 10 years. Colonoscopy uses a long, flexible tube equipped with a camera and light, to view the entire colon. If polyps or abnormal structures are found, surgical tools are passed through the tube to remove polyps or take tissue samples for analysis. Typically, any polyps found in the colon are removed during colonoscopy and examined for pre-cancerous changes, known as dysplasia. If high-grade dysplasia is detected, a follow-up colonoscopy is required to monitor the condition.
Colorectal cancers are caused by mutations that increase the rate of cellular division. Some of these mutations can be INHERITED from parents. Examples of inherited colorectal cancers include:
– Familialadenomatous polyposis, or FAP: a condition caused by mutations in the APC gene. The APC protein acts as a tumor suppressor, keeping cells from growing and dividing too fast. Mutations in APC result in uncontrolled cell division, causing HUNDREDS of polyps to grow in the colon. FAP patients usually develop colon cancer by the age of 40.
– Lynch syndrome: another inherited condition caused by changes in genes that normally help repair DNA damages. A faulty DNA repair results in increased rate of mutations. Patients are at high risks of colorectal cancer as well as other types of cancers.
In most cases, however, the mutations that lead to cancer are ACQUIRED during a person’s life rather than being inherited. The early event is usually a mutation in the same APC gene that is responsible for FAP. While FAP is a rare condition, APC mutations are very common in sporadic colorectal cancers.
Apart from genetic predisposition, other risks factors for colon cancer include: aging, high-red meat and low-fiber diets, obesity, alcohol use, smoking, diabetes, and inflammatory intestinal conditions, such as ulcerative colitis and Crohn’s disease.
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Breast reconstruction surgery is a vital component of breast cancer treatment plan. Breast reconstruction surgery can be done immediately after mastectomy or in a delayed operation depending on whether post-mastectomy radiation therapy will be needed. Immediate reconstruction offers better aesthetic results if radiation is not needed. When radiation is required, delayed reconstruction is preferred to avoid possible complications.
Breast Implant
Breast implant involves insertion of a breast prosthesis made of synthetic material. A typical breast implant has a silicone shell and is filled with saline or silicone gel.
Advantages: requires short initial hospital stay, simplest of all procedures, no additional scars, no other sites on body to heal except for the breast.
Disadvantages: As a result of the body’s response to foreign material, the implant may be squeezed within scar tissues leading to distorted shape (capsular contracture), leak, rupture and infection. In fact as many as half of all women will require surgery to remove the implant later in life.
Natural Tissue Breast Reconstruction Surgery
These techniques use body’s own tissue for the new breast. A section (flap) of skin, fat, and possibly muscle is harvested from a donor site elsewhere in the body and transferred to the chest to make the new breast. Possible tissue donor sites include: lower abdomen, back, buttock and area above it, inner thigh. Lower abdomen is by far the preferred donor site as it comes with a bonus of a flatter tummy after operation.
Advantages compared to breast implants: The use of autologous tissue allows the reconstruction of a breast which looks and feels most like a normal breast. More importantly, this also solves the problem of the new breast being rejected by body’s immune system.
Disadvantages compared to breast implants: Longer initial hospital stay; additional scar on the donor site; donor site may be weaken due to loss of muscle.
Below we discuss different techniques available for breast reconstruction surgery with lower abdomen as the donor site, in order from the oldest to the newest, with advantages and disadvantages of each as compared to each other.
TRAM flaps
Transverse Rectus Abdominus Myocutaneous flap – the first of all natural tissue reconstruction technique.
Fig. 1 : Pedicle TRAM flap breast reconstruction surgery. Click on image to see it on Alila Medical Media website where the image is also available for licensing.
The original (pedicled) TRAM flap (Fig. 1) : A section of skin and fat is cut from the lower abdomen. One of the rectus abdominis muscles (six-pack muscles) is divided in the lower abdomen. The lower end of the muscle remains attached to the skin/fat tissue. This is the flap that is now attached to the body by the upper end of the muscle at its original position. The flap is rotated together with the muscle and passed under the skin to the new location in the chest. Here it is shaped to form the new breast. The flap is supplied by the blood vessels that run inside the rectus abdominis muscle. A piece of synthetic mesh is placed in the abdomen to provide support for the abdominal wall that is now weakened due to removal of the muscle.
Advantages: Relatively simpler procedure compared to newer techniques as microsurgery expertise is not required, more surgeons are able to offer this procedure.
Disadvantages: Significant loss of muscle from the abdomen makes the abdominal wall weakened and subject to risk of hernia; attachment of the flap to the body makes it harder to be configured into desired shape.
Free TRAM Flaps
An improvement from the original TRAM flaps technique. In this procedure, a section of skin, fat and part of rectus abdominis muscle with blood vessels within it, is separated completely from the body (hence “free”) and transferred to the breast location. The blood vessels of the flap (deep inferior epigastric artery and vein) are connected to recipient vessels in the breast using microsurgery technique.
Fig. 2 : Free TRAM flap breast reconstruction surgery. Click on image to see it on Alila Medical Media website where the image is also available for licensing.
Advantages: Free flaps are easier to sculpt into desired shape; blood supply is more robust.
Disadvantages: Microsurgery expertise is required; weakened abdominal wall due to muscle loss.
A modification of the procedure called muscle-sparing (MS) free TRAM flap is designed to remove only a minimum amount of muscle.
DIEP Flaps
Deep Inferior Epigastric Perforator flaps. A significant improvement from TRAM flaps. In this procedure the blood vessels (deep inferior epigastric artery and vein) are carefully dissected from the muscle. An incision is made in the rectus abdominis muscle for dissection of blood vessels but no muscle is taken out. The flap contains skin, fat, blood vessels but no muscle. The blood vessels of the flap are then connected to recipient vessels in the breast using microsurgery technique (Fig. 3 and Fig. 5).
Fig. 3 : DIEP flap breast reconstruction surgery. Click on image to see it on Alila Medical Media website where the image is also available for licensing.
Advantages: all advantages of a free flap; no muscle taken from donor site.
Disadvantages: Microsurgery required; longer operation time; not offered by many surgeons.
SIEA Flaps
This procedure is based on a different set of blood vessels – Superficial Inferior Epigastric Artery and Vein. These vessels supply the skin and fat tissue of the abdomen and run within the fat layer. With this flap, the abdominal muscle is left untouched, and therefore this is the preferred technique whenever it’s possible. The reason why this is not widely used is because these vessels are not large enough in 90% of patients. Commonly, these superficial blood vessels are approached first during surgery. If the surgeon sees that they are big enough, a SIEA flap will be used, if not, a DIEP flap will be performed instead.
Fig. 4 : SIEA flap breast reconstruction surgery. Click on image to see it on Alila Medical Media website where the image is also available for licensing.
Advantages: all advantages of a free flap; no muscle taken from donor site; no damage to the muscle.
Disadvantages: only possible in about 10% of women; microsurgery required; not offered by many surgeons.
Fig. 5 : Comparing the flaps from different breast reconstruction surgery techniques. Click on image to see it on Alila Medical Media website where the image is also available for licensing.
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The number of cells in a tissue is determined by the balance between cell division and cell death. Uncontrollable cell division leads to formation of abnormal growths called tumors. Tumors can be benign or malignant. Benign tumors are slow-growing and constrained by surrounding connective tissue so they do not spread to other organs. They can still be harmful or even kill by pressing on nearby nerves, brain tissue or blood vessels. Examples of benign tumor include pituitary tumors which may press on optic nerves and cause loss of vision. Cancers are malignant tumors – tumors that can spread beyond of the limit of original organ where it comes from and to other organs of the body.
How cancer starts
Cancer starts from a damage in the DNA of a cell. This DNA damage is called mutation. Mutations happen when the cell duplicates its DNA prior to cell division and makes mistakes. These damages are usually detected and repaired before the cell can divide but sometimes, some of them may be ignored and transferred to daughter cells.
If the mutation is located in one of many genes that control the cell cycle, it may affect the regulation of cell cycle in the cell carrying it, and make the cell divide faster than it supposed to. Usually, one mutation is not enough to cause cancer, but as it makes the cell cycle control less reliable, many more DNA damages/mutations would go unnoticed. Cancer is usually the result of accumulation of many mutations of genes involved in cell cycle control and DNA repair. This commonly happens over a long period of time, over many rounds of cell divisions, and this explains why cancers are more common in older people.
Fig. 1 Cancer cells reproduce to from tumor.Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.
Some people are said to be predisposed to cancer. This is because they are born with a mutation that makes them more likely to develop a certain type of cancer. This mutation alone is not enough to cause cancer but it starts the process of making cells cancerous. The person carrying it is one step further down the road towards developing a cancer than others who do not have the mutation.
Genes that are mutated in cancer
Three main classes of genes that are found mutated in cancers:
Proto-oncogenes – when mutated become oncogenes. Most cells do not divide until a growth factor binds to a receptor on its surface and instruct it to do so. Growth factor binding activates a cascade of events preparing the cell for division. Proto-oncogenes encode for normal growth factors and growth factor receptors. Oncogenes encode for abnormal versions of these. These malfunctional growth factors and receptors instruct the cells to divide non-stop causing cancer. A well known example of oncogene is ras, which encodes for a mutated growth factor receptor.
Tumor suppressors (TS) genes – these encode for cell cycle inhibitors, a class of molecules that prevent the progression of the cell cycle. Many of these arrest the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes. A famous TS gene is p53, which is found mutated in majority of cancers including colon, brain, breast, lung cancers and leukemia.
DNA repair genes –these encode for enzymes that repair damage in DNA before the cell can divide. Mutations in these genes lead to accumulation of mutations that eventually make the cell cancerous.
How cancer spreads
Cancer cells do not stick together like normal cells, they move and invade nearby tissues, organs, this is local spread. They may also spread to further away organs by means of blood and lymph circulation, this is systemic spread. Metastasis is the spreading of cancers to non-adjacent organs. Cancer cells from the original tumor (primary cancer) can break out and maybe taken up by a blood or a lymph vessel for a ride throughout the body. They can then squeeze out from the vessels into other tissues and start a new tumor growth in the new location which will become secondary cancer.
Fig. 2 : Cancer cells squeeze through the wall of blood and lymph capillary. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.
Where do cancers usually spread and why?
While travelling in the bloodstream, cancer cell usually stops at the first place where the vessel getting so narrow that it gets stuck. As blood flow from most organs goes to the capillaries of the lungs, this is where cancers spread the most. Lungs are indeed the most common site of secondary cancers.
Fig. 3 : Primary cancer from the pancreas metastases to the lungs through the bloodstream. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.
Likewise, while travelling in the lymphatic system, cancer cells commonly get stuck in nearest lymph nodes, where the vessels get narrower. This is the reason why surgeons usually remove nearby lymph nodes when removing tumors.
Most cells divide periodically to give rise to two daughter cells. A cell cycle covers a period of time from one cell division to the next.
Phases of cell cycle
– First gap phase – G1 phase – cell grows in size and prepares for DNA replication. G1 checkpoint (see below) makes sure everything is ready for DNA replication. This is also the period where the cells carry out their normal metabolic roles for the body.
– Synthesis phase – S phase – DNA replication occurs, the cell makes a second, identical set of DNA molecules. It now has two sets, ready to distribute to the two daughter cells.
– Second gap phase – G2 phase – preparation for cell division, cell synthesizes proteins/enzymes that are necessary for mitosis. G2 checkpoint (see below) makes sure the cell is ready for division.
– Proper cell division – M phase – mitosis phase where the mother cell is split into two daughter cells by the process of mitosis. Mitosis has four phases on its own : prophase, metaphase, anaphase and telophase (commonly with cytokinesis). Fig. 1 : A typical cell cycle with four phases. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.
The G1, G2 and S phases are together called interphase – the time in between M phases. The length of cell cycle varies greatly from one cell type to another with the length of G1 phase being most variable.
G0 (G zero) phase
In an adult multicellular organism, it’s very common for cells to stop dividing permanently or temporary for a certain period of time. Such cells are said to be in G0 phase (resting phase), or to be quiescent. They usually enter G0 phase from G1 phase (Fig. 2). Fully differentiated skeletal muscle cells and neurons are post-mitotic and stay in G0 for the rest of their life. Some other cells can be stimulated to get back to G1 when needed (e.g. liver cells). Finally, there are cells that never enter G0 and continue dividing for life (e.g. epithelial cells). Fig. 2 : A cell cycle diagram showing exit to G0. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.
Cell cycle checkpoints
Checkpoints are control mechanisms to ensure that cell division proceeds with highest accuracy. Before going into the next phase, the cell has to check if everything is ready, scan for DNA damage and activate repair if needed. If the cell is not ready, cell cycle will be arrested. This is to ensure that damaged or incomplete DNA molecules are not passed onto daughter cells.
There are three main checkpoints in the cell cycle:
– G1 checkpoint ( also called restriction point in animal cell, or start point in yeast) is located at the end of G1 phase, before the entrance to S phase. This is the point when the cell needs to make a decision to divide or not depending on the environmental factors. The cell may proceed to cell division (to S phase), delay division waiting for more signals (stay in G1), or enter resting phase (to G0 phase).
– G2 checkpointis located at the end of G2 phase, before commitment to M phase. Here the cell needs to check if everything is ready for mitosis. Most importantly, it has to check for any DNA damages that may have occurred during DNA synthesis (S phase). If damages are detected, cell cycle will be arrested at this point.
– Metaphase checkpoint (spindle checkpoint) is located in metaphase, before the onset of anaphase. This is to make sure that ALL the chromosomes are properly aligned at the metaphase plate before the sister chromatids can be pulled apart in anaphase. If a chromosome is “late” to come to its position, the metaphase will be arrested waiting for it. This is how the cell ensures that the two daughter cells will have exactly the same set of chromosomes. Failure of this would result in a daughter cell with an extra chromosome and the other missing a chromosome, a situation that is deleterious for both.
Molecular regulators of cell cycle
Cyclins and cyclin-dependent kinases (CDKs) form cyclin-CDK complexes that determine the progression of cell cycle through different phases. Cyclins are regulatory subunits of the complexes and are expressed only at specific stages of cell cycle. CDKs are catalytic subunits of the complexes and are activated by binding to cyclins. Upon binding to a cyclin, CDK acquires ability to phosphorylate target proteins. CDKs are constitutively expressed. Combination of different CDKs to different cyclins determine substrate specificity of the complexes.
Inhibitors of cell cycle or tumor suppressors –a class of molecules that prevent the progression of the cell cycle. Many of these arrest the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes.
Regulation of cell cycle and cancer
The number of cells in a tissue is determined by the balance between cell division and cell death. The proportion of cells actively dividing versus those in resting (G0) phase plays an important role and must be strictly controlled. Disregulation of cell cycle would result in uncontrollable cell division and formation of abnormal growths called tumors. Tumors that can spread to other organs are cancers. Cancerous cells are characterized by an inability to stop diving and to enter resting phase.
