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Cervical Cancer

Ellie Perez

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Introduction into Cervical Cancer

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Every Year approximately 163.5 of 100,000 men and women die from cancer [1]. Cancer is the second most common cause of death in the United States right behind heart disease. Cancer is a disease that is characterized by the uncontrolled growth of abnormal cells. This characteristic is due to changes in genes and will result in the cells ignoring signals that would normally tell the cells to stop dividing. This unique characteristic of cancer cells is the cause of tumor formation and spreading. There are various risk factors for developing cancer including age, sex, lifestyle, genetics, etc. That being the case, women have the additional risk of being diagnosed with cervical, breast, endometrial, and ovarian cancer. The American Cancer Society predicts that roughly 13,170 cases of cervical cancer will by diagnosed and 4,250 women will die from cervical cancer in 2019.  

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Cervical cancer effects the cells that line the cervix of a woman. The cervix is the lower region of the uterus which connects to the vagina. It is divided into two areas: the endocervix, made up of glandular cells and the exocervix, made up of squamous cells. The area where these two areas meet is called the transformation zone which is where cervical cancer usually begins. There are a few different types of cervical cancer depending on how they look under the microscope. The first and most common type is squamous cell carcinomas. This type originates in the exocervix. The second type is adenocarcinomas which develop in the gland cells of the endocervix. The least common type is adenosquamous carcinomas which is a mix of both squamous and glandular cells [2].     

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Cervical_cancer.jpg

Risk Factors and Causes of Cervical Cancer

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There are many risk factors associated with cervical cancer. Like with all other cancers, smoking is a great risk factor for cervical cancer as it damages DNA in the cervix cells. A weakened immune system is also a risk factor since they body is not fully capable of fighting off infection. Some other risk factors include chlamydia infection, poor diet, obesity, long term oral contraceptive use, IUD, multiple pregnancies, teenage pregnancies, and family history [2].

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Research has shown that one of the primary causes for cervical cancer involves the human papillomaviruses (HPV). HPV is a common sexually transmitted infection. The Center for Disease Control and Prevention states that 79 million Americans are infected with HPV. There are about 15 genotypes of carcinogenic HPV that can infect women and lead to cervical cancer [4]. HPV16 and HPV18 are two types of HPV that cause 50% and 20% of cervical cancer, respectively [8]. E5, E6 and E7 are the primary genes associated with HPV and act as oncoproteins. Cervical cancer, however, does not arise until decades after the initial HPV exposure. Unfortunately, this along with the detection in late stage due to inadequate screening, can lead to the high number of deaths in women from this cancer. When detected in the early stage there is a 92% survival rate, when it has spread to surrounding areas there is a 56% survival rate, and when it is in the late stage there is a 17% survival rate [2]. Along with the initial HPV infection, abnormal protein expression and disrupted or irregular signaling pathways promote the development and progression of cervical cancer. Proteins such as URG4, SPAG5, and Six1 are all involved in this progression. Pathways such as the Hippo/YAP pathway and PI3K/Akt pathway are affected and lead to improper signaling that contribute to cervical cancer progression.

Symptoms

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Early Signs

  • Abnormal vaginal bleeding: arises from the uterus

    • Menstrual bleeding that is longer and heavier than usual

    • Bleeding after intercourse

    • Bleeding after menopause

    • Bleeding between periods

  • Increased vaginal discharge

  • Pain during sexual intercourse due to tumor growth in vaginal area

  • Back pain

 

Advanced Signs

  • Weight loss

  • Fatigue

  • Persistent pelvic and/or back pain due to pressure from the growing tumor on the spine or nerves

  • Swelling and pain of the legs due to tumor growth which presses against nerves in the pelvic wall and puts pressure on the lymph nodes or veins

  • Leakage of urine

  • Bone fractures

Signaling Pathways Involved

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Signaling Pathways and Dysregulations Involved in Cervical Cancer

 

With the onset and progression of cervical cancer, comes a variety of irregularities amongst proteins, genes, and signaling pathways. Sperm associated antigen 5 (SPAG5) is found to be upregulated and upregulator of cell proliferation 4 (URG4) is overexpressed in cervical cancer patients. SPAG5 down regulates the target of the mTOR signaling pathway which as a result, protects the cells from apoptosis [5]. URG4 promotes cell proliferation. Both of these, therefore, promote the progression of cervical cancer.

 

As discussed previously, HPV is a virus which leads to the expression of oncoproteins E5, E6, and E7 which in turn can modify multiple signaling pathways in the body. E5 can increase the activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) signaling pathway and mitogen-activated protein kinase pathways while inhibiting apoptotic pathways. E6 induces the PI3K/Akt, Wnt, and Notch signaling pathways, increases telomerase activity, and inactivates tumor protein 53 (p53), PDZ proteins, and some miRNAs. E6 also plays a role in the disruption of the Hippo/YAP pathway. E7 can also stimulate the PI3K/Akt pathway as well as deregulate miRNA expression [8].

 

Normal Signaling VS Signaling in Cervical Cancer

 

Normally, p53 is a tumor suppressor that when activated can slow down the cell cycle and allow any damaged DNA to be properly repaired or initiate apoptosis. Therefore, when p53 is inactivated by E6, there is a buildup of abnormal cells which is ultimately what cancer is.

 

The PI3K/Akt signaling pathway is one that plays a principal role is cell proliferation, cell growth, cell survival, and apoptosis. Essentially, PI3K regulates Akt which has numerous downstream targets that lead to the above outcomes. When this pathway is overregulated, it may become a cancer survival pathway. E6 has been found to activate this pathway in various forms. It is able to do this through direct interaction with PI3K. E6 is also able to block TSC1/2 activity which promotes mTORC1 activity leading to cell growth. It can also inhibit the activity of BAD/BAX and p53 to promote cell survival and reduce apoptosis, respectively [8].

          

The Hippo/YAP pathway generally controls organ size and tumorigenesis. It is able to do this through a kinase cascade that ultimately inactivates YAP proteins which controls the development of cervical cancer. E6 is able to promote YAP activity and sustain increased levels of YAP by preventing proteasome-dependent YAP degradation [7]. This will lead to cell proliferation in cervical cancer patients. This pathway, along with the PI3K/Akt pathway, are depicted below, as well as the effects of E6 of various parts of each pathway.

Cerv_cancer_diagram.png

Prevention and Therapeutic Intervention

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There are preventative measures women can take, including prophylactic HPV vaccines, new HPV screening tests, and the traditional Pap test, to reduce their chances greatly of being diagnosed with cervical cancer [9]. A pap smear will look for abnormal cells and pre-cancerous changes allowing for early detection. Women are recommended to start getting pap smears at the age of 21 and get one every 3 years until the age of 29 and then every 5 years after that. 50% of patients that are diagnosed with cervical cancer have never had a pap smear and only 45% of patients are diagnosed in the early stage. With a simple pap smear, patients can increase their survival rate by nearly 50%.

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Chemotherapy can be an effective therapeutic intervention however; single chemotherapeutic agents can only extend patients lives by 1 year [8]. This is because it can lead to drug resistance through its ability to activate certain signaling pathways that induce cell growth and proliferation. Certain antiviral therapies have been used to fight cervical cancer. For example, Cidofovir restores p53 which can induce apoptosis eliminating abnormal cells. Along with this, some chemicals can be used to reverse certain pathways like PI3K/Akt. SC-66 and MK-2206, allosteric Akt inhibitors, combined with glucose analog 2-deoxyglucose in C33A cells resulted in inhibition of the PI3K/Akt pathway therefore decreasing cell viability and inhibiting migration [8].

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References

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  1. Cancer Statistics. (n.d.). Retrieved from https://www.cancer.gov/about-cancer/understanding/statistics

  2. Cervical Cancer. (n.d.). Retrieved from https://www.cancer.org/cancer/cervical-cancer.html

  3. Sexually Transmitted Diseases - Information from CDC. (n.d.). Retrieved from https://www.cdc.gov/std/

  4. Schiffman, M., Castle, P. E., Jeronimo, J., Rodriguez, A. C., & Wacholder, S. (2007). Human papillomavirus and cervical cancer.(9590), 890-907.

  5. Yuan, L. -., Li, J. -., Zhang, L., Wang, J. -., Wan, T., Zhou, Y., . . . Zheng, M. (2014). SPAG5 upregulation predicts poor prognosis in cervical cancer patients and alters sensitivity to taxol treatment via the mTOR signaling pathway. Cell Death and Disease, 5, 8.

  6. Zhang, L., Huang, H., Zhang, L., Hou, T., Wu, S., Huang, Q., . . . Liu, J. (2014). URG4 overexpression is correlated with cervical cancer progression and poor prognosis in patients with early-stage cervical cancer., 885.

  7. He, C., Mao, D., Hua, G., Lv, X., Chen, X., Angeletti, P. C., . . . Wang, C. (2015). The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Molecular Medicine, 7(11), 1426-1449.

  8. Chen, J. (2015). Signaling pathways in HPV-associated cancers and therapeutic implications. Reviews in Medical Virology, 25, 24-53.

  9. Smith, J. S., Brewer, N. T., Saslow, D., Alexander, K., Chernofsky, M. R., Crosby, R., . . . Casey, B. R. (2013). Recommendations for a national agenda to substantially reduce cervical cancer.(8), 1583-93.

  10. Tan, J., Zhang, C., & Qian, J. (2011). Expression and significance of Six1 and ezrin in cervical cancer tissue. Tumor Biology, 32(6), 1241-7.

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