Cancer Genetics and Epigenetics 2024, Vol.12 http://www.medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
Cancer Genetics and Epigenetics 2024, Vol.12 http://www.medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in cancer genetics, cancer epigenetics, clinical pharmacology, cancer biology at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of Cancer Genetics and Epigenetics Email: edit@cge.medscipublisher.com Website: http://www.medscipublisher.com/index.php/cge Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Cancer Genetics and Epigenetics (ISSN 2369-2995) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is aimed to publish all works in the areas that with quality and originality, with a scope that spans the areas of cancer genetics and cancer epigenetics. It is archived in LAC (Library and Archives Canada) and deposited in CrossRef. The journal has been indexed by ProQuest as well, expected to be indexed by PubMed and other datebases in near future. All the articles published in Cancer Genetics and Epigenetics are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Cancer Genetics and Epigenetics (online), 2024, Vol. 12, No. 1 ISSN 2369-2995 http://www.medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content The Application Prospects of Immunomodulators in Cancer Treatment TinaWang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 1-7 The Etiology and Epidemiology Exploration of Cervical Cancer Rain Wang, Kendra Ding, Jessi Zhang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 8-14 The Exploration of Immunotherapy Methods for Endometrial Cancer Ningmeng Guo, Jialan Guo, Shoukai Wang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 15-26 Development and Influencing Factors of Female Cancers Shu Guo, Danni Gu, Xi Chen Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 27-36 The Application and Challenges of Emerging Technologies in Early Diagnosis and Screening of Gastric Cancer: From Molecular Markers to Imaging Advances AnitaWang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 37-46 High-Throughput Sequencing Technology: A New Chapter in Epigenetics and Disease Research JimMason Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 47-54 A New Perspective on Revealing Tumor Heterogeneity through Single Cell RNA Sequencing TaoChen Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 55-65 Multiplex Immunofluorescence in Colorectal Cancer: A Retrospective Analysis from SCOT and QUASAR 2 Trials JimMason Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 1, 66-69
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 1 Review and Progress Open Access The Application Prospects of Immunomodulators in Cancer Treatment TinaWang Biotechnology Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, China Corresponding author email: 1507666916@qq.com Cancer Genetics and Epigenetics, 2024, Vol.14, No.1 doi: 10.5376/cge.2024.12.0001 Received: 20 Nov., 2023 Accepted: 21 Dec., 2023 Published: 01 Jan., 2024 Copyright © 2024 Wang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang T., 2024, The application prospects of immunomodulators in cancer treatment, Cancer Genetics and Epigenetics, 14(1): 1-7 (doi: 10.5376/cge.2024.12.0001) Abstract Cancer is a significant global health issue with increasing incidence and mortality rates. Traditional cancer treatment methods, including surgical removal, radiotherapy, and chemotherapy, have achieved some efficacy to a certain extent but still pose many limitations and side effects. Therefore, finding new treatment strategies has become a focal point in current cancer research. Immune modulators, as a novel approach to cancer treatment, have the characteristics of regulating the immune system and enhancing the body's immune response, showing promising results in clinical practice. However, there is currently some controversy and uncertainty regarding the prospects of immune modulators in cancer treatment. Thus, this review aims to summarize the application prospects of immune modulators in cancer treatment, explore their mechanisms of action, clinical application status, and development trends, providing a reference for further research and clinical practice. Keywords Immune modulators; Cancer treatment; Immune system; Body immune response; Development trends Cancer causes millions of deaths annually, and despite the partial success of traditional cancer treatments such as surgery, radiotherapy, and chemotherapy, they have limitations and side effects. These include damage to normal cells, the development of drug resistance, and the recurrence of tumors post-treatment. Therefore, finding new treatment strategies has become a key focus in current cancer research. Immune modulators have emerged as a crucial area of study in the field of cancer treatment. The immune system plays a critical role in combating cancer by recognizing and eliminating abnormal cells, thus preventing the development and spread of tumors (Omar et al., 2019). However, cancer cells often evade attacks from the immune system through various mechanisms, leading to immune tolerance and escape. Therefore, by modulating the immune system and enhancing the body's immune response, it is possible to effectively suppress the growth and metastasis of tumors. The mechanisms of action of immune modulators are diverse, including the activation of immune cells, enhancement of anti-tumor immune responses, and inhibition of tumor immune escape. The application of these immune modulators provides new perspectives and approaches for cancer treatment. Currently, immune modulators have shown encouraging results in clinical applications. Immune checkpoint inhibitors have been widely used in the treatment of various cancers, such as melanoma, non-small cell lung cancer, and renal cell carcinoma (Shiravand et al., 2022), achieving significant therapeutic effects. Additionally, other types of immune modulators, such as cytokines and tumor vaccines, have demonstrated certain potential in clinical trials. However, immune modulators still face challenges and limitations in cancer treatment. Variability in immune responses among different tumor types and individuals necessitates further research and optimization of the selection and application of immune modulators. The side effects and safety of immune modulators also require careful consideration, especially in long-term and combination therapies. Additionally, the efficacy and resistance issues of immune modulators need further investigation and resolution. This review provides an overview of immune modulators, with a focus on their application in cancer treatment, including their anti-tumor mechanisms and application cases in different types of cancer. Simultaneously, it discusses the development trends and prospects of immune modulators, encompassing the development of novel immune modulators, the advancement of personalized immune therapies, and the combined application of
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 2 immune modulators with other treatment methods. Finally, the review summarizes the prospects of immune modulators in cancer treatment, offering insights into future research directions. It is hoped that this review provides a comprehensive understanding of the application prospects of immune modulators in cancer treatment, offering a scientific basis for clinical practice, providing more effective and safe treatment strategies for cancer patients, and contributing to further advancements in the field of cancer research. 1 Overview of Immune Modulators 1.1 Definition and classification of immune modulators GImmune modulators refer to drugs or therapeutic methods capable of regulating the function of the immune system. Different types of immune modulators may vary in treatment mechanisms, indications, and side effects. Therefore, their selection and application should be based on specific circumstances. Immune checkpoint inhibitors are immune checkpoints that activate immune cells to attack tumors by blocking inhibitory signals between tumor cells and immune cells. Common immune checkpoints include anti-CTLA-4 antibodies (such as ipilimumab), anti-PD-1 antibodies (such as pembrolizumab), and anti-PD-L1 antibodies (such as atezolizumab). Cytokines are a class of protein molecules that can enhance the activity of immune cells and promote immune responses (Liu et al., 2022). Common cytokines include interferons (such as interferon-α and interferon-γ), interleukins (such as interleukin-2 and interleukin-12), among others. Tumor vaccines represent a kind of vaccine capable of eliciting a specific immune response in the body, recognizing and eliminating tumor cells. Tumor vaccines may include tumor-related antigens, tumor cells, or their products, among other components. Apart from the types of immune modulators mentioned above, there are also other types such as immune cell therapy (e.g., CAR-T cell therapy), and immune adjuvants (e.g., liposomes and adjuvants), etc. 1.2 Mechanisms of action of immune modulators Different types of immune modulators may have distinct mechanisms of action, and these mechanisms can be influenced by various factors such as dosage, administration route, and the target of treatment. Therefore, when using immune modulators, it is necessary to make selections and applications based on specific circumstances. Certain immune modulators can inhibit the activity of the immune system, reduce the function and quantity of immune cells, thereby diminishing the intensity of immune responses. This mechanism is commonly employed in the treatment of autoimmune diseases. Other immune modulators can enhance the activity of the immune system, promote the function and quantity of immune cells, thereby intensifying the effectiveness of immune responses. This mechanism is often used in the treatment of infectious diseases and tumors, such as interferons and interleukins. Certain immune modulators can regulate the balance of the immune system, maintaining appropriate control during immune responses. This mechanism is often employed in the treatment of diseases associated with immune dysregulation, such as immune checkpoint inhibitors (e.g., anti-CTLA-4 antibodies and anti-PD-1 antibodies) (Seidel et al., 2018). Some immune modulators can enhance the immune system's memory and recognition capabilities for specific antigens, thereby strengthening the persistence and specificity of immune responses. This mechanism is commonly used in the fields of vaccines and immune cell therapy. 1.3 The current clinical application of immunomodulators Immunomodulators are widely utilized in the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and others. Commonly used immunomodulators include corticosteroids, immunosuppressants (such as cyclosporine A, methotrexate), and others. Immunomodulators are employed post-organ transplantation to suppress the host immune system's rejection response toward the transplanted organ. Commonly used immunosuppressants include cyclosporine A, tacrolimus, and others. Immunomodulators play a crucial role in the treatment of hematological malignancies such as leukemia and lymphoma. For instance, immunostimulants like interferons and interleukins can be employed to enhance the immune system's ability to attack tumors. Immunomodulators are also utilized in the treatment of diseases related
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 3 to immune dysregulation, such as immunodeficiency disorders and allergic conditions. Immune checkpoint inhibitors (such as anti CTLA-4 antibodies and anti PD-1 antibodies) are a commonly used class of immune modulators. Furthermore, immunomodulators are used to boost the effectiveness of vaccines, thereby enhancing vaccine protection. For example, adjuvants (such as aluminum salts) can augment the immunogenicity of vaccines. 2 Immunomodulator Application in Cancer Treatment 2.1 Mechanisms of immunomodulators in antitumor therapy The mechanisms through which immunomodulators act in anticancer treatment primarily involve enhancing immune responses, suppressing immune inhibition, and modulating immune balance. Immunomodulators can augment the body's immune system's ability to recognize and attack tumor cells. For instance, immunostimulants like interferons and interleukins can activate immune cells, increase the production and activation of tumor-specific T cells, and promote immune cell-mediated cytotoxicity against tumor cells. There are some immunosuppressive factors in the tumor microenvironment, such as the overexpression of immune checkpoint molecules (e.g., PD-1, CTLA-4), which inhibit the activation and cytotoxicity of immune cells against tumor cells (Huang et al., 2020). Immunomodulators can counteract the effects of immunosuppressive factors by inhibiting their actions, relieving the inhibition of immune cells, and enhancing the immune cells' ability to attack tumor cells. For example, anti-PD-1 antibodies and anti-CTLA-4 antibodies can block the PD-1 and CTLA-4 signaling pathways, restoring the activation and cytotoxic functions of immune cells. During the process of tumor development, the immune system often exists in a state of immune balance, wherein tumor cells evade immune system attacks by modulating the functions of immune cells. Immunomodulators can adjust this immune balance, enabling the immune system to regain its ability to target tumor cells. For example, immunosuppressants can inhibit the inhibitory functions of immune cells, enhancing the cytotoxic effects of immune cells against tumor cells. It should be noted that different types of tumors and individual immune states may have an impact on the anti-tumor effect of immune modulators. Therefore, when employing immunomodulators for anticancer treatment, personalized treatment plans should be formulated based on individual circumstances, and close monitoring of the patient's immune status and drug-related side effects is essential. 2.2 Application cases of immunomodulators in the treatment of different types of cancer The application of immunomodulators may vary across different types of cancer, and specific treatment plans need to be determined based on the patient's condition and immune status. Additionally, the use of immunomodulators may give rise to certain side effects, such as immune-related toxic reactions. Therefore, close monitoring of the patient's immune status and drug-related side effects is crucial throughout the course of treatment. PD-1 antibodies (such as Pembrolizumab and Nivolumab) have been widely employed in the treatment of melanoma (Huang et al., 2021). Melanoma patients often exhibit demonstrate of PD-1, and anti-PD-1 antibodies can block the binding of PD-1 to its ligand PD-L1, restoring T cell cytotoxicity against tumor cells, thereby enhancing therapeutic efficacy. CTLA-4 antibody (such as Ipilimumab) is used in the treatment of metastatic melanoma (Figure 1). CTLA-4 is an immune inhibitory molecule, and anti-CTLA-4 antibodies can block CTLA-4's function, enhancing T cell activation and cytotoxicity, thereby inhibiting the growth and spread of melanoma. Interferon is an immunostimulant widely utilized in the treatment of renal cell carcinoma. Interferon enhances the immune cell's ability to attack tumor cells and inhibits the growth and spread of tumor cells. Interleukin-2 (IL-2) is an immunostimulant used in the treatment of melanoma and renal cell carcinoma. IL-2 activates immune cells, increases the production and activation of tumor-specific T cells, and promotes the immune cell-mediated cytotoxicity against tumor cells.
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 4 Figure 1 FDA approved immune checkpoint inhibitors Note: Pembrolizumab, Nivolumab, and Cemiplimab as anti PD-1 antibodies; Ipilimumab as anti CTLA-4 antibody and Atezolizumab, Avelumab, and Durvalumab as anti PD-L1 antibodies 2.3 Advantages and challenges of immunomodulators in cancer treatment Immunomodulators in cancer treatment offer advantages including targeting the immune system, providing durable therapeutic effects, and being applicable to various cancer types. Immunomodulators can directly influence the immune system, activating or inhibiting specific immune cells or molecules, thereby enhancing the immune system's ability to attack tumors. Compared to traditional chemotherapy and radiation therapy, immunomodulators can generate sustained therapeutic effects. Once the immune system's ability to target tumors is activated, immune cells can continually eliminate tumor cells, reducing the risk of recurrence and metastasis. Immunomodulators find applications in the treatment of various cancer types, including melanoma, lung cancer, breast cancer, colorectal cancer, among others. This makes immunomodulators a widely applicable and versatile treatment approach. One of the challenges in cancer treatment with immunomodulators is the development of resistance, where some patients may exhibit resistance to immunomodulator therapy (Da Silva et al., 2019). Tumor cells can evade immune cell attacks by altering immune escape mechanisms, thereby diminishing the effectiveness of immunomodulators. Additionally, the use of immunomodulators may trigger immune-related toxic reactions, such as autoimmune diseases caused by immune cell attacks on normal tissues. These toxic reactions can negatively impact the quality of life and treatment outcomes for patients. Furthermore, individual variations in patient responses to immunomodulators may exist. Some patients may respond well to immunomodulator therapy, while others may not. The high cost of immunomodulator treatment may limit access for some patients. Additionally, some immunomodulators have not been approved by insurance companies, making it difficult for patients to obtain these treatments. 3 Trends in the Development of Immunomodulators 3.1 Development of novel immunomodulators The development of novel immunomodulators represents a crucial research direction in the field of cancer treatment. Scientists are continually striving to identify new immunomodulators to enhance the effectiveness of cancer therapy and reduce side effects. These research endeavors hold the promise of bringing about breakthroughs in cancer treatment. However, it is important to note that the development of novel immunomodulators is a complex and lengthy process, necessitating rigorous laboratory research and clinical trials before they can be ultimately applied in clinical settings.
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 5 CAR-T cell therapy is a treatment method that utilizes engineered T cells to target and attack cancer cells (Jiang et al., 2022). Scientists are actively researching ways to enhance the design of CAR-T cells to improve their therapeutic efficacy and safety. While immune checkpoint inhibitors have achieved significant success, a portion of patients still does not respond effectively to this treatment. Consequently, researchers are investigating the combination of immune checkpoint inhibitors with other treatment modalities such as chemotherapy, radiation therapy, and targeted therapy to enhance overall treatment outcomes. Scientists are also on the lookout for novel immunomodulators to activate the immune system's ability to target tumors. This includes the search for new immune checkpoint molecules, immune cell activators, tumor-associated antigens, and more. The emergence of gene editing technologies (such as CRISPR-Cas9) provides a new tool for the development of immunomodulators. Researchers can use gene editing techniques to modify the functions of immune cells, enabling them to better target and attack cancer cells. The microbiome plays a crucial role in immune system regulation. Scientists are exploring how to enhance the immune system's ability to target tumors by modulating the gut microbiome. 3.2 Development of personalized immunotherapy Personalized immunotherapy is an approach to individualized treatment based on patient-specific differences. It involves designing precise treatment plans considering factors such as the patient's genetic background, immune status, and other variables, aiming for optimal therapeutic outcomes. Personalized immunotherapy represents a significant trend in the future of cancer treatment. Although it currently faces numerous challenges, continuous technological advancements are expected to bring about more precise and effective treatment strategies in clinical practice. With the continuous advancement of molecular biology and genomics technologies, scientists can acquire patients' molecular characteristics through methods such as gene testing and genetic sequencing. Based on this information, individualized treatments like targeted therapy can be implemented. While immunotherapeutic drugs show promising prospects in cancer treatment, there are still cases where the therapeutic outcomes are suboptimal. With in-depth research on the mechanisms of cancer immunotherapy, scientists can develop more precise treatment plans from the perspective of individual patient differences, such as personalized application of immune checkpoint inhibitors. Cellular immunotherapy involves utilizing biotechnology to transform a patient's own immune cells into cells with anti-tumor capabilities, which are then reintroduced into the patient's body for treatment (Huang et al., 2019). Personalized cellular immunotherapy can be precisely designed based on factors such as the patient's immune status and the characteristics of immune cells, aiming to achieve better treatment outcomes. 3.3 Combination application of immunomodulators with other treatment methods The combined application of immunomodulators with other treatment methods represents a comprehensive therapeutic strategy aimed at enhancing treatment outcomes through the synergistic effects of different therapeutic approaches. The combined use of immunomodulators with other treatment methods requires the individualized design of treatment plans based on the specific conditions of each patient, along with vigilant monitoring and assessment in clinical practice. Additionally, the combination approach may increase treatment side effects and risks, necessitating guidance under the supervision of a qualified medical professional. Chemotherapy is a treatment method that utilizes chemical drugs to kill cancer cells. However, chemotherapy can also cause damage to normal cells and the immune system. Immunomodulators can enhance immune system function, improve the body's tolerance to chemotherapy, and enhance the effectiveness of chemotherapy. Targeted therapy is a treatment method that inhibits the growth and spread of cancer cells by targeting specific molecular targets on cancer cells. Immunotherapy activates the immune system, enhancing its ability to attack cancer cells. The combination of these approaches can improve treatment outcomes and reduce the occurrence of drug resistance (Barbari et al., 2021).
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 6 Radiation therapy is a treatment method that uses high-energy radiation to kill cancer cells (Figure 2). However, radiation therapy can also cause damage to normal cells and the immune system. Immunomodulators can enhance immune system function, improve the body's tolerance to radiation therapy, and enhance the effectiveness of radiation therapy. Surgery is a treatment method that involves the removal of tumor tissue. Immunotherapy can activate the immune system, eliminating residual cancer cells and reducing the risk of recurrence and metastasis. The combination of these approaches can improve the effectiveness of surgery and reduce the likelihood of postoperative recurrence. 3.4 Potential applications in cancer prevention and early diagnosis Immunomodulators have potential applications in cancer prevention and early diagnosis. By modulating the function of the immune system, immunomodulators can enhance the body's ability to clear precancerous lesions, thereby preventing their progression into cancer. For example, certain immunomodulators can augment immune cell recognition and cytotoxicity against abnormal cells, reducing the development of precancerous lesions. Immunomodulators can reduce the risk of cancer by enhancing the functionality of the immune system, thereby improving the body's ability to eliminate cancer cells. For instance, certain immunomodulators can boost immune cell attack on cancer cells, reducing their survival and spread. By modulating the immune system's function, immunomodulators can enhance the body's ability to recognize cancer cells, thereby helping to detect cancer early. For example, some immunomodulators can enhance immune cell recognition of cancer cell-specific antigens, thereby increasing the detection rate of early-stage cancer. 4 Summary and Outlook Cancer poses a significant global health challenge, and traditional treatment methods such as chemotherapy and radiation therapy have certain limitations. Immunotherapy, as an emerging treatment strategy, has made significant strides by harnessing the patient's own immune system to target cancer cells. Immune checkpoint inhibitors, among the most successful immunotherapeutic approaches, activate the patient's immune system to attack cancer cells by inhibiting the action of immune checkpoint molecules. These drugs have demonstrated notable therapeutic effects in various cancer types, including melanoma and non-small cell lung cancer. However, immunotherapy still faces challenges such as immunoresistance and side effects. Immunotherapy can lead to immune resistance in some patients. Future research will explore the mechanisms underlying immune resistance and seek methods to overcome it, such as developing new immunomodulators, implementing combination therapy strategies, and enhancing immune cell functionality. The application of immunotherapy needs to consider individual differences and tumor characteristics. Future research will focus on developing personalized immunotherapy strategies, including predictive models based on tumor genomics and immunohistology, as well as tailored treatment plans for individual patients. Figure 2 Cystic fibrosis
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 1-7 http://www.medscipublisher.com/index.php/cge 7 The potential application of immunomodulators in early cancer diagnosis and prevention holds promise (Zhu et al., 2023). Subsequent research will investigate the mechanisms of action of immunomodulators in early cancer diagnosis and prevention, along with the development of corresponding treatment strategies. The application of immunomodulators requires consideration of their safety and side effects. Future research will continue to focus on the safety of immune modulators and seek methods to reduce side effects, enhancing the acceptability and effectiveness of treatments. In conclusion, the outlook for the application of immunomodulators in cancer treatment is very promising, but further research and validation are needed. With the continuous progress of scientific and technological advancements, we anticipate the emergence of more innovative immunomodulators and treatment strategies, bringing improved therapeutic outcomes and survival rates for cancer patients. References Barbari C., Fontaine T., Parajuli P., Lamichhane N., Jakubski S., Lamichhane P., and Deshmukh R.R., 2020, Immunotherapies and combination strategies fo Acknowledgments From the selection of the topic for this study to the final completion of the project, gratitude is extended to Ms. Yeping Han for her valuable input and suggestions. r immuno-oncology, Int. J. Mol. Sci., 21: 5009. https://doi.org/10.3390/ijms21145009 PMid:32679922 PMCid:PMC7404041 Da Silva C.G., Camps M.G.M., Li T.M.W.Y., Chan A.B., Ossendorp F., and Cruz L.J., 2019, Co-delivery of immunomodulators in biodegradable nanoparticles improves therapeutic efficacy of cancer vaccines, Biomaterials, 220: 119417. https://doi.org/10.1016/j.biomaterials.2019.119417 PMid:31419588 Jiang Y., Wen W.H., Yang F., Nie D., Zhang W.H., and Qin W.J., 2022, Research progress of multi-target CAR-T cell therapy for cancer, Zhongliu Fangzhi Yanjiu (Cancer Research on Prevention and Treatment), 49(7): 709-714. Huang D., Gong C., and Song E.W., 2019, Adoptive immune cell therapy for malignant tumors moves from “individualization” to “precision”, Shengming Kexue (Chinese Bulletin of Life Sciences), 31(7): 651-659. Huang Q., Zheng Y., Gao Z., Yuan L., Sun Y., and Chen H., 2021, Comparative efficacy and safety of PD-1/PD-L1 inhibitors for patients with solid tumors: a 8: 86. https://doi.org/10.3389/fonc.2018.00086 systematic review and bayesian network meta-analysis, J. Cancer, 12: 1133. https://doi.org/10.7150/jca.49325 PMid:33442411 PMCid:PMC7797652 Seidel J., Otsuka A., and Kabashima K., 2018, Anti-PD-1 and Anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations, Front. Oncol., PMid:29644214 PMCid:PMC5883082 Huang S.J., Qiu X.D., Li W.Y., Tang K.R., Wu Q., Deng H.Y., Deng L.F., and Huang L., 2020, Cellular crosstalk and tumorigenic mechanisms in tumor targeting immune checkpoints and the tumor microenvironment, The FEBS Journal, 286(18): 3540-3557. https://doi.org/10.1111/febs.15000 cell differentiation in peripheral blood, Shengming Gongcheng Xuebao (Chinese Journal of Biotechnology), 38(9): 3329-3343. microenvironment, Shengming Kexue (Chinese Bulletin of Life Sciences), 32(4): 315-324. Liu L., Jiao P.T., Wang M., Li J., Sun L., Fan W.H., and Liu W.J., 2022, Effects of chicken interferon-γ and interleukin-2 on cytokines related to Th1 Omar H.A., El-Serafi A.T., Hersi F., Arafa E.S.A., Zaher D.M., Madkour M., Arab H.H., and Tolba M.F., 2019, Immunomodulatory MicroRNAs in cancer: PMid:31306553 Shiravand Y., Khodadadi F., Kashani S.M.A., Hosseini-Fard S.R., Hosseini S., Sadeghirad H., Ladwa R., Byrne K.O., and Kulasinghe A., 2022, Immune checkpoint inhibitors in cancer therapy, Current Oncology, 29(5): 3044-3060. https://doi.org/10.3390/curroncol29050247 PMid:35621637 PMCid:PMC9139602 Zhu X.X., Chen H.Z., Cui K.Y., Zhong W., Peng X.S., and Zhou Y.B., 2023, Current situation and prospect of exosomes application in tumor diagnosis and treatment, Zhongguo Yixue Daobao (China Medical Herald), 20(9): 41-45.
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 8-14 http://www.medscipublisher.com/index.php/cge 8 Research Report Open Access The Etiology and Epidemiology Exploration of Cervical Cancer Rain Wang, Kendra Ding, Jessi Zhang Zhuji Xiongcheng Jianmin Med. Ltd., Zhuji, 31180, China Corresponding author email: jessi.j.zhang@foxmail.com Cancer Genetics and Epigenetics, 2024, Vol.12, No.1 doi: 10.5376/cge.2024.12.0002 Received: 23 Nov., 2023 Accepted: 29 Dec., 2023 Published: 08 Jan., 2024 Copyright © 2024 Wang et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang R., Ding K., and Zhang J., 2024, The etiology and epidemiology exploration of cervical cancer, Cancer Genetics and Epigenetics, 12(1): 8-14 (doi: 10.5376/cge.2024.12.0002) Abstract Cervical cancer is a common gynecological malignancy that predominantly affects young women, posing serious threats to women's health and lives. Studies in etiology and epidemiology have revealed the relationship between HPV infection and cervical cancer, marking a significant breakthrough in its prevention and treatment. HPV vaccines and screening technologies have been widely applied in clinical practice, substantially reducing the incidence and mortality rates of cervical cancer. Furthermore, research has identified associations between cervical cancer occurrence and development with factors such as smoking, high-fat diets, and vitamin deficiencies. To enhance the treatment effectiveness and prevention of cervical cancer, China needs to bolster fundamental research and clinical practice. In future studies, China should further explore other factors associated with cervical cancer and devise corresponding treatment and prevention strategies. Strengthening fundamental research and clinical practice to improve treatment effectiveness and prevention levels constitutes a crucial task for the present and future. The purpose of this review is to foster a better understanding of cervical cancer, its etiology, and contributing factors, contributing to cervical cancer treatment and prevention efforts while drawing greater attention to women's health. Keywords Cervical cancer; HPV infection; Etiology; Epidemiology Cervical cancer is one of the most common malignancies among women and a significant global women's health issue according to statistics from the International Agency for Research on Cancer, approximately 500 000 women worldwide die from cervical cancer each year. In developing countries, cervical cancer remains a leading cause of female mortality. Although the mortality rate from cervical cancer has significantly decreased in developed nations, there still exists a notable incidence and mortality rate. Hence, studying the etiology and epidemiology of cervical cancer holds crucial significance in devising better preventive and therapeutic strategies. The occurrence of cervical cancer is associated with various factors, primarily the human papillomavirus (HPV) infection. Additionally, other elements such as genetic predisposition, long-term contraceptive use, early onset of sexual activity, multiple pregnancies, smoking, among others, can influence cervical cancer development. Therefore, exploring the etiology of cervical cancer can deepen our understanding of its pathogenesis, facilitating the search for new treatment and prevention approaches. Epidemiological studies of cervical cancer are equally vital. Disparities in cervical cancer incidence and mortality rates across different regions and populations are linked to socio-economic factors, educational levels, and healthcare services. Understanding the patterns of cervical cancer epidemiology can assist in formulating more targeted preventive and treatment strategies. Research into cervical cancer holds significant importance concerning health issues, prevention and control, etiological investigations, early diagnosis, and treatment. Continual in-depth research enables better comprehension and management of this serious public health concern. By thoroughly investigating the etiology and epidemiology of cervical cancer, we can provide more accurate and effective strategies for prevention and control, ultimately reducing its incidence and mortality rates, and make contributions to women's health and social development. This review aims to explore the etiology and epidemiology of cervical cancer, providing readers with comprehensive insights to better understand its mechanisms and patterns. This understanding serves as a basis for scientifically informed preventive and treatment strategies.
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 8-14 http://www.medscipublisher.com/index.php/cge 9 1 Etiological Study of Cervical Cancer 1.1 Relationship between HPV virus and cervical cancer The Human Papilloma virus (HPV) is a DNA virus transmitted through sexual contact, primarily responsible for the occurrence of cervical cancer. The extent and types of HPV infections lead to varying degrees of cervical lesions. Among them, high-risk HPV types (such as HPV16, 18) are the primary pathogens causing cervical cancer. The longer the duration of HPV infection, the higher the risk of cervical cancer development. HPV is prevalent and infects a wide range of individuals. In sexually active women, the incidence of HPV infection can exceed 70%. Although most people will clear themselves after being infected with HPV, some people may develop cervical cancer after infection. Hence, HPV infection stands as a major factor contributing to the development of cervical cancer (Schiffman et al., 2007). There are many mechanisms between HPV infection and cervical cancer, mainly including the following aspects: HPV virus infection can cause atypical proliferation of cervical epithelial cells, thereby forming cervical lesions. High-risk HPV types disrupt the gene expression in cervical cells, prompting cell proliferation and transformation, ultimately forming cancerous cells. HPV infection also inhibits the autophagy and apoptosis of cervical cells, thereby enhancing the survival and proliferation of cancer cells (Figure 1). Figure 1 The development process of cervical cancer (Source: https://zhuanlan.zhihu.com/p/63054607) At present, there are multiple HPV vaccines available in the market that effectively prevent HPV infection and the occurrence of cervical cancer. HPV vaccines can prevent infections caused by high-risk HPV types, thereby reducing the risk of cervical cancer. According to relevant research data, receiving the HPV vaccine can decrease the incidence of cervical cancer by over 70%. Additionally, screening and treating HPV infe ctions are crucial measures for preventing and treating cervical cancer. Currently, the World Health Organization recommends cervical cancer screening for women aged 20 to 65, which includes Pap smears and HPV testing. If cervical abnormalities or HPV infections are detected, timely treatment is necessary to prevent the progression of lesions into cervical cancer. HPV infection stands as one of the primary factors leading to cervical cancer. HPV vaccines, screening, and treatment are crucial means of preventing and treating cervical cancer, effectively reducing the risk of its occurrence (Zhou et al., 2023). 1.2 Genetic factors and cervical cancer incidence Genetic factors also play a role in the occurrence of cervical cancer. Some studies suggest an increased risk of developing cervical cancer for individuals with a family history of the disease. Moreover, specific gene mutations are associated with cervical cancer. For instance, mutations in the BRCA1 gene can elevate the risk of developing cervical cancer. BRCA1 is a tumor suppressor gene that inhibits tumor formation by regulating pathways involved in DNA repair and cell apoptosis. Mutations in BRCA1 may compromise its tumor-suppressing function, thereby
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 8-14 http://www.medscipublisher.com/index.php/cge 10 increasing the risk of cervical cancer. Research indicates that individuals with BRCA1 gene mutations have 2-3 times higher risk of developing cervical cancer compared to the general population. Furthermore, other gene mutations may also be linked to cervical cancer. For example, mutations in the MLH1 gene could heighten the risk of cervical cancer, while the absence of the GSTT1 gene might potentially reduce the risk. Future studies focusing on genetic aspects are necessary to explore the impact of gene mutations on cervical cancer occurrence, aiding in the development of more targeted preventive and therapeutic strategies. Currently, some genetic testing companies offer mutation tests targeting genes like BRCA1, enabling women to understand their risk of cervical cancer for more precise preventive and treatment measures. Genetic factors are significant influencers in the development of cervical cancer. Mutations in genes like BRCA1 can increase the risk of developing cervical cancer, and genetic testing can help women understand their susceptibility to cervical cancer for more precise preventive and therapeutic approaches. Apart from genetic factors, various other elements such as dietary habits, lifestyle, and environmental pollution may affect gene expression, indirectly impacting cervical cancer occurrence. Further research into these factors' impact on gene expression and function is crucial for better prevention and treatment of cervical cancer (Trimble et al., 2015). 1.3 Other related factors 1.3.1 Long-term use of oral contraceptives There is a certain correlation between long-term use of oral contraceptives and the incidence of cervical cancer. Studies have found that the risk of developing cervical cancer increases in women who have used oral contraceptives for more than 5 years. The mechanism of oral contraceptives involves suppressing ovulation to prevent pregnancy. However, long-term usage might also affect the growth and differentiation of cervical epithelial cells, thereby increasing the risk of cervical cancer. 1.3.2 Early initiation of sexual activity The early initiation of sexual activity is associated with the occurrence of cervical cancer. During adolescence, the cervix is not fully mature, making it less resistant to pathogens and more susceptible to infections. Additionally, early initiation of sexual activity might lead to dysplasia in cervical epithelial cells, further increasing the risk of cervical cancer. Multiple pregnancies are also linked to the incidence of cervical cancer. Research indicates that multiple pregnancies can elevate the risk of developing cervical cancer, possibly due to the damage and repair processes in cervical epithelial cells caused by multiple pregnancies, consequently increasing the risk of cervical cancer. 1.3.3 Smoking and other factors Smoking is another significant factor contributing to cervical cancer. Studies suggest that smoking increases the risk of cervical cancer, possibly because carcinogens in tobacco can directly or indirectly affect the growth and differentiation of cervical epithelial cells. Besides the mentioned factors, various other elements such as immune function, nutritional status, among others, might influence cervical cancer occurrence. Further research is needed to explore the impact of these factors on cervical cancer incidence to develop more precise preventive and treatment strategies. In summary, long-term use of oral contraceptives, early initiation of sexual activity, multiple pregnancies, smoking, and other factors could influence cervical cancer occurrence. Understanding these related factors can help women take effective preventive measures to reduce the risk of cervical cancer. Moreover, future research is crucial to delve deeper into the mechanisms behind cervical cancer occurrence to provide more accurate preventive and treatment measures. 2 Factors Influencing the Incidence and Mortality of Cervical Cancer Cervical cancer is one of the important health issues for women worldwide. It is a malignant tumor that is related to multiple factors in its occurrence and development. Annually, over 500 000 women globally succumb to cervical cancer, with a majority occurring in low and middle-income countries. The global annual incidence of
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 8-14 http://www.medscipublisher.com/index.php/cge 11 cervical cancer is around 15 to 20 cases per 100 000 individuals, with a mortality rate of 8 to 10 cases per 100 000 individuals. In high-income countries, the incidence and mortality rates of cervical cancer are relatively lower. Disparities exist in these rates among different regions and demographics. Higher rates in low to middle-income countries correlate with factors like healthcare services, preventive measures, and screening access. Strengthening global awareness, promoting preventive measures like screenings and vaccinations among women, can effectively reduce cervical cancer incidence and mortality. Moreover, enhancing healthcare services and coverage on a global scale is essential to offer comprehensive and superior health services to women. Additionally, further research into cervical cancer's etiology and treatment methods is necessary to provide more effective means for prevention and treatment (Bosch et al., 2022). Some studies indicate that socioeconomic factors significantly influence cervical cancer incidence and mortality. Incidence and mortality rates are higher in low and middle-income countries compared to high-income countries, possibly due to inadequate healthcare services, preventive measures, and screening in these countries. Additionally, educational attainment is linked to cervical cancer incidence and mortality. Research suggests that women with higher education levels have a lower risk of cervical cancer. This could be attributed to the higher likelihood of health education acceptance and screenings among educated women, aiding in the early detection and treatment of cervical cancer. Healthcare services are also among the significant factors impacting cervical cancer incidence and mortality. Studies suggest that improving the coverage and quality of screening and treatment effectively reduces cervical cancer incidence and mortality. Moreover, vaccination stands as an effective method for preventing cervical cancer, yet its accessibility remains lower in low and middle-income countries. Although cervical cancer has high global incidence and mortality rates, advancements in medical technology and preventive measures are gradually improving this situation. For example, enhancements in screening and treatment technologies effectively prevent and treat cervical cancer, and vaccination remains an effective preventive measure. In addition, global promotion and popularization, raising women's health awareness, can also help reduce the incidence and mortality of cervical cancer. Variations in cervical cancer occurrence exist across regions and demographics, associated with factors like age, ethnicity, and reproductive history. Factors influencing cervical cancer incidence and mortality include socioeconomic status, education, and healthcare services. Future efforts should focus on global awareness campaigns, enhancing women's health consciousness, promoting preventive measures like screenings and vaccinations to reduce cervical cancer occurrence and mortality. Simultaneously, bolstering global healthcare services and coverage to provide comprehensive and superior health services to women is essential (Arbyn et al., 2020). 3 Future Research Directions 3.1 Strengthening fundamental research for innovative therapeutic and preventive strategies Cervical cancer's prevention and treatment remain a global challenge. While China has acquired certain treatment and prevention strategies, substantial work lies ahead. Thus, intensifying fundamental research on cervical cancer etiology to explore novel treatment and prevention strategies becomes imperative. In-depth exploration of the relationship between HPV infection and cervical cancer occurrence is crucial for China. This entails uncovering fresh treatment and prevention approaches. While HPV vaccines serve as a vital preventive measure, not all individuals can access them. Hence, China needs further research into HPV infection treatments, exploring novel vaccines and therapies. Additionally, elucidating the HPV virus's mechanisms of action, specifically its impact on cell proliferation and apoptosis, is necessary to identify new treatment and prevention strategies. Augmenting research on other factors and their correlation with cervical cancer, such as lifestyle, environmental influences, and genetics, is pivotal. Studying the impact of these factors on cervical cancer will facilitate the exploration of relevant treatment and prevention strategies. For instance, research could examine the preventive role of dietary improvements and lifestyle changes in cervical cancer or delve into the impact of environmental pollution, enabling the formulation of appropriate prevention and treatment strategies.
Cancer Genetics and Epigenetics 2024, Vol.12, No.1, 8-14 http://www.medscipublisher.com/index.php/cge 12 Advancing studies in genetics, metabolism, and immunology is crucial to unearth new treatment and prevention strategies. Research into genetic variations and expressions concerning cervical cancer development could pave the way for targeted treatment strategies. Similarly, exploring the relationship between metabolites, immune factors, and cervical cancer could reveal potential treatment and prevention avenues. Strengthening fundamental research in cervical cancer etiology to explore new treatment and prevention strategies is critical for its prevention and control. Continuously exploring innovative treatment and prevention strategies can enhance the cure and survival rates of cervical cancer, offering patients more hope and possibilities (Gao and Zhang, 2023). 3.2 Enhancing screening and diagnostic techniques for prevention and treatment Early screening and diagnosis play a vital role in preventing and treating cervical cancer, requiring continued improvement in techniques. While there have been significant advancements in cervical cancer screening and diagnostic technologies, numerous challenges persist, demanding further enhancement of their accuracy and reliability. China needs to research more precise and effective HPV screening techniques to further improve the accuracy and reliability of HPV screening. At present, commonly used HPV screening techniques include liquid thin-layer cytology, HPV-DNA detection, and protein chips. These technologies have been widely applied in clinical practice, but there are still some problems, such as high false positive and false negative rates, complex operations, etc., which need to be improved in accuracy and reliability (Huh et al., 2015; Chuang et al., 2016). Exploration of more sensitive and specific diagnostic techniques like liquid-based cytology, biomarkers, and imaging is vital to improve early diagnosis rates and treatment outcomes for cervical cancer. Although liquid-based cytology has seen significant accuracy improvements, issues persist, such as a high false-positive rate and diagnostic results influenced by collected cell quantity and quality. Hence, there's a need for further refinement. Biomarkers and imaging are essential research areas. Biomarkers, detecting specific proteins, genes, or metabolites, offer high specificity and sensitivity. Imaging technologies like magnetic resonance imaging and ultrasound can determine tumor location, size, morphology, and its relationship with surrounding tissues. While these technologies are extensively used clinically, further research and refinement are needed to enhance their accuracy and reliability. Furthermore, promoting and popularizing advanced treatment and surgical techniques like microwave therapy, laser treatment, and surgical excision are essential to improve treatment effectiveness and survival rates. These techniques are widely used clinically but require further research and improvement to enhance efficacy and safety (Cuzick et al., 2008; Pfaendler and Tewari, 2016). Enhancing screening and diagnostic techniques for cervical cancer prevention and control is critical. Continuous exploration of new technologies and methods to improve their accuracy and reliability is necessary to provide better treatment and recovery for patients. Simultaneously, strengthening healthcare professionals' training and education to enhance their understanding and treatment levels for cervical cancer is essential to offer patients comprehensive and superior medical services (Table 1). Table 1 Preventive screening in women of different age groups Population (Age) Recommended screening methods Propose <21 No screening - 21~29 Cytology was screened individually every 3 years - 30~65 None (Best), or cytology alone every 3 years (acceptable) HPV screening alone is not recommended >65 If the previous screening has sufficient negative results, there is no need to screen again If the previous screening has sufficient negative results, there is no need to screen again Female gender after the hysterectomy No screening is required For women with no cervix and no CIN 2, CIN 3, adenocarcinoma or cervical cancer Women vaccinated with the HPV vaccine Follow the screening strategy for the corresponding age -
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