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The Open Colorectal Cancer Journal, 2014, 7, 1-4 1

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Colorectal Cancer Causes and Treatments: A Minireview

Anita Nasrallah and Mirvat El- Sibai*

Department of Natural Sciences, Lebanese American University, Beirut 1102 2801, Lebanon

Abstract: Colon cancer is the cancer of the epithelial cells lining the colon. This type of cancer occurs in many people
that are either genetically predisposed or exposed to risk factors. Colorectal cancer is mainly divided into different stages
according to invasiveness and metastatic ability of the tumor. Many mutations are acquired, leading to this malignancy.
Treatment of colorectal cancer range from surgery in early stages to palliative care in most advanced stages. In this
minireview, we summarize the latest findings on colorectal cancer.
Keywords: Colon cancer, Oncogenes, Apoptotic proteins, genetics, Inflammatory Bowel Diseases, Crohn’s disease.

Colorectal cancer, commonly known as bowel cancer, well associated with this type of cancer. The most common
occurs in the colon, rectum, or appendix. Genetic analysis is known as the Lynch syndrome, or the hereditary
shows that tumors in these three locations are genetically of nonpolyposis colorectal cancer (HNPCC) [4]. Familial
the same cancer [1]. Colorectal cancer is the second most adenomatous polyposis (FAP) [10] and Gardner syndrome
commonly diagnosed cancer in females, the third in males [11] are both as well strongly associated with this type of
[2], and the forth around the world [3]. More than a million cancer.
cases are yearly detected globally [4]. It is widespread in
developed countries, where around 60% of the cases were Inflammatory Bowel Diseases
diagnosed [5], most of which lead to death [6].
A third cause is the incidence of the Inflammatory Bowel
There are several causes for the onset of colorectal Diseases, such as ulcerative colitis and Crohn’s disease [12].
cancers, which are nowadays better diagnosed and classified The longer the onset of these diseases [13], and the worse the
according to several criteria. Consistently, different inflammation [14] will directly affect the risk of having
treatments and prognostic measures are currently used to try colorectal cancer. However, only about 2% of this cancer is
and successfully cure this type of cancer [4]. associated with the previously mentioned diseases [12].

CAUSES AND PREDISPOSITION PATHOGENESIS

Colorectal cancer occurs in a wide range of people. Most Colorectal cancer originates from the epithelial lining,
of them were previously, and might still be exposed to most often as a consequence of mutations in the Wnt
numerous risk factors. The rest are either genetically signaling pathway. These mutations can be either acquired or
predisposed, or associated with other bowel diseases. inherited. They mostly occur in the intestinal gland stem
cells [15].
Risk Factors
It is estimated that more than 80% of patients with Tumor Suppressor Genes
colorectal cancer were exposed to a number of risk factors, In all colorectal cancer, APC is the most commonly
such as male gender, older age [4], high intake of red meat or mutated gene. It produces the APC protein, which prevents
fat, smoking and obesity [7]. The risk of alcohol increases at the accumulation of the β-catenin protein by binding to and
more than a drink per day [8]. Also, around 10% of these degrading it. In the absence of APC protein, β-catenin highly
cases are related to insufficient activity [9]. accumulates in the cytoplasm, translocates to the nucleus,
and binds to DNA, thus activating the transcription of
Genetics several genes. These genes are responsible for stem cell
Around 18% of all cases are patients with a family renewal and differentiation. However, when improperly
expressed at elevated levels they cause cancer [16].
history. Thus, they have a two to three-fold risk increase than
other people. Furthermore, three main genetic diseases are Some colorectal cancers have high β-catenin levels due
to mutations in its gene CTNNB1, and not in the APC gene.
*Address correspondence to this author at the Department of Natural
These mutations block the degradation of β-catenin. Other
Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran 1102 colorectal cancers have mutations in other APC analogues,
2801, Beirut, Lebanon; Tel: +961-1-786456; Ext: 1253; such as NKD1, TCF7L2, AXIN1, or AXIN2. Another tumor
Fax: +961-1-867098; E-mail: [email protected] suppressor, PTEN, normally inhibits the overexpressed

1876-8202/14 2014 Bentham Open

2 The Open Colorectal Cancer Journal, 2014, Volume 7 Nasrallah and El- Sibai

oncogene PI3K. However if PTEN is mutated, it becomes precise. T stands for the depth of the tumor, and to which
deactivated [16]. level did it penetrate the colon wall. N refers to the
involvement of lymph nodes. M stands for the degree of
Apoptotic Proteins metastases that took place or whether the tumor has spread
or not [22].
Other than the defects mentioned above, additional
mutations must take place for the cells to acquire more Another less used system is the Duke’s system [23]. It
cancerous characteristics. One of these mutations occurs in was then modified and became the Modified Dukes Staging
the p53 protein, which is produced by the TP53 gene. This System. This system classifies the tumors under four main
categories, i.e. A, B, C, and D. Modified Duke Stage A is the
apoptotic protein monitors normal cell division. It kills the
tumors that only reach the mucosal wall. B is the ones that
cells if they acquire any defect in the Wnt signaling pathway.
penetrate through and out of the wall. C is the advancement
Its mutation will change the tissue from a non-invasive of the tumor into the lymph nodes. D is when tumors are
adenoma into an invasive carcinoma [17]. In some cases, the depicted in other organs, such as the liver, lung and bone
gene encoding for BAX, another protective protein, is [24].
mutated, instead of the TP53 gene [16].
Other apoptotic proteins are frequently mutated and SYMPTOMS AND DIAGNOSIS
deactivated in colorectal cancers. A major protein is the Signs and symptoms of colorectal cancer greatly depend
TGF-β, which in at least half of colorectal cancers has a on its location and ability to metastasize. These include
deactivating mutation. In some cases, TGF-β is not the fever, loss of appetite, weight loss, constipation, and blood in
protein mutated, but its downstream protein SMAD (16). stool. In people older than fifty, common symptoms are
Another protein is the DCC protein, or Deleted in Colorectal nausea, vomiting anaemia, and rectal bleeding [25]. It is
Cancer. It acquires a deletion of its chromosomal segment important to note that the most evident symptoms are weight
[18]. loss and rectal bleeding [26]. Without them all other
symptoms can be indicative of several different
Oncogenes gastrointestinal diseases [27].
Normal genes that encode proteins, known as Colorectal cancers occurring on the right side of the
oncoproteins, responsible for the regulation of cell growth colon, i.e. the ascending colon and cecum, usually cause
and differentiation are known as proto-oncogenes. They are severe fecal obstruction and anaemia. This is because these
mainly involved in signal transduction. When activated, tumors tend to grow outward from a location of the bowel
increased expression or mutations will result in the wall. However, left-sided tumors, i.e. tumors of the
transformation into oncogenes, which are tumor-inducing descending colon, cause constipation. These tumors are most
agents [19]. These are overexpressed in colorectal cancer, likely circumferential [28].
such as genes encoding the proteins PI3K, RAF, and RAS The first step towards diagnosis is to take tumor biopsy
[20]. during wither colonoscopy or sigmoidoscopy. After
confirming the presence of the cancer, imaging tests are
Under normal conditions and in response to growth
performed of the patient’s chest, abdomen and pelvis, to
factors, these proteins will stimulate the cell to divide. determine the extent of the disease. These tests include CT
Acquired mutations will lead to the over-activation of cell scan, PET, and MRI. Based on these results, the physician
proliferation. In some cases, the chronological order of can establish a clear idea of the stages of the cancer,
mutations is crucial for the progression of cancer. To depending on the TNM system of classification [4].
illustrate, if at first a KRAS mutation occurred, this will lead
to a self-limiting borderline lesion. On the other hand, if the PATHOLOGY OF THE TUMOR
KRAS mutation occurs after an APC mutation, it often leads
to cancer [21]. After biopsy or surgery, a pathology report explicitly
determines the cell type and grade of the tumor. In 95% of
All the previously discussed mutations occur in one type the cases, the colon cancer type is adenocarcinoma [29]. It
of colorectal carcinomas, known as the hypermutated tumor originates from the glandular epithelium, invading the wall
type. These tumors have mutated forms of BRAF, TCF7L2, and infiltrating all layers. Tumor cells have irregular
SLC9A9, MSH3, MSH6, TGFBR2, and ACVR2A. Genome- structures and might secrete mucus. Depending on the
scale analysis reveals that the non-hypermutated tumor type predominant cellular pleomorphism, gland architecture, and
contains mutated ARIDIA, ATM, SOX9, and FAM123B. secretion of mucus, adenocarcinoma is separated into three
What is in common among the genes in both carcinomas is differentiation levels: poorly, moderately, and well
their involvement in the TGF-β and WNT signaling differentiated. Other than adenocarcinoma, rare types of
pathways. This, in turn, will result in the hyper activity of the colorectal cancer include squamous cell carcinoma and
central player in colorectal cancer, MYC [1]. lymphoma [30].
Besides, the majority of colorectal cancer tumors are
CLASSIFICATION OF COLORECTAL CANCER cyclooxygenase-2, or COX-2, positive. This enzyme is
The most widely used classification system is the TNM abundantly found in cancerous tissue of the colon. It aids in
Staging System. It is considered the most descriptive and abnormal cell growth [31].
Colorectal Cancer Causes and Treatments: A Minireview The Open Colorectal Cancer Journal, 2014, Volume 7 3

TREATMENT AND PROGNOSIS PREVENTION

As any other type of cancer, the treatment of colorectal The most important ways to prevent colorectal cancer are
cancer depends on its advancement. At early stages, surgery a healthy lifestyle, appropriate medication, and continuous
is mostly curative. At later stages when the cancer is screening.
metastatic, physicians tend to treat their patients by trying to
prolong their life and keep them comfortable [32]. Life Style
Dietary recommendations include reducing the
Surgery consumption of red meat and increasing the intake of fruits,
Patients with localized colorectal cancer undergo vegetables, fibers and whole grains [43]. Physical activity
surgeries to extract the tumor. It is either done by laparotomy also helps reducing the risk of colorectal cancer [44].
or laparoscopy, which is a minimally invasive procedure. If
other tumors are metastasized to the lungs or liver, they are Medication
removed surgically [4]. People at high risk of having colorectal cancer are
advised to take aspirin and celecoxib. They both appear to
Chemotherapy decrease the risk factor. Nevertheless, these drugs are not
recommended to those at average risk [45]. Vitamin D,
In some cases, chemotherapy is used before surgery. This
especially its blood concentration, and Calcium intake are
will help shrink the tumor before eradicating it. In other
also associated with lower risks of colorectal cancer [46, 47].
cases where the cancer has metastasized and entered the
lymph nodes, chemotherapy is a must to help increase the
Screening
life expectancy of the patient. Drugs may include oxaliplatin,
irinotecan, leucovorin, UFT, capecitabine, or 5-fluorouracil. Several screening methods are applied nowadays, and
Monoclonal antibodies against molecular targets include they proved to be helpful in reducing death by the early
cetuximab, panitumumab, or bevazicumab [33]. detection [48]. The three main tests are fecal occult blood
Understanding better the tumor biology and molecular testing of the stool, sigmoidoscopy, and colonoscopy [49].
pathways and mechanisms effectively led to the discovery of The newest screening method is the M2-PK test to stool
novel agents that specifically target molecular elements of samples. The M2-PK enzyme biomarker is highly sensitive
cancer cells. This has helped improving the efficacy of drug- to colorectal cancer. It is able to detect bleeding and non-
based chemotherapy that is nowadays combined with bleeding types, which a fecal occult blood test cannot do
targeted monoclonal antibodies. Research is being [50].
extensively done to try and use cell signaling pathways as
targets for colorectal cancer treatment, even though these CONFLICT OF INTEREST
pathways highly intercorrelate and crosstalk [34]. The authors confirm that this article content has no
conflicts of interest.
Radiation
ACKNOWLEDGEMENT OF FUNDING
Combining chemotherapy and radiation might be helpful.
But, in most cases, this is not used as curative technique, The department of Natural science, the Lebanese
since the bowels are highly sensitive to radiation [35]. American University.

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Received: September 20, 2013 Revised: November 19, 2013 Accepted: November 19, 2013

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