Laura Kim

Background: Colorectal cancer is the collective term for colon and rectal cancer. It is the second most lethal cancer and the third most common cancer worldwide.^1,2,3 Right now, the most effective treatment for these patients is to use standard chemotherapy, typically 5-fluorouracil and oxaliplatin.² These patients are initially responsive to the chemotherapy combination, but quite a few patients become resistant.² There are many risk factors such as obesity and lack of physical exercise,⁴ but a considerable risk factor to note is gut microbiome dysfunction.⁵ Alteration of gut microbiota or microbiota dysbiosis was shown to be significantly associated with the onset and progression of colorectal cancer. This has led to the discovery of Fusobacterium nucleatum. This bacterium is thought to be involved in autophagy, a pathway that cells undertake to survive through stimulating the expression of certain autophagic proteins. Autophagy is used in normal cells as a survival mechanism, but cancer cells can also use this to proliferate throughout our body.

Objectives: The purpose of this study is to further understand Fusobacterium nucleatum and its role in modulating autophagy for carcinogenesis.

Search Methods: An online search using PubMed was used only using articles within the past 5 years. Keywords searched were “fusobacterium nucleatum”, “colorectal cancer”, and “autophagy”.

Results: F. nucleatum is related to decreased levels of BECN1, a protein part of the autophagosome. This inverse relationship shows that autophagy is imperative in the defense against pathogens.⁶ It also happens to modulate autophagy through the upregulation of CARD3, which binds directly to LC3, an autophagic protein. It also causes deceased levels of E-cadherin, a protein important in contact inhibition. This shows that F. nucleatum plays a role in metastasis through autophagy.⁷ Higher levels are also related to higher levels of chemoresistance in those who are experiencing recurrence of CRC.² It targets and upregulates the TLR4 and MYD88 innate signaling pathway. This selectively causes the downregulation of microRNAs 4802 and 18a*. Downregulation of these microRNAs cause upregulation of ATG7 and ULK1, both key proteins that promote autophagy. Increased autophagy allows the tumor cells from evading apoptosis, leading to increased chemoresistance and increased recurrence. Thus, increased levels of F. nucleatum in colorectal cancer patients result in increased levels of standard chemotherapeutic resistance.² Despite increased levels of chemoresistance related to increased levels of F. nucleatum, there is a positive correlation between the bacterium and immune checkpoint therapy, a cancer therapy that was not beneficial in CRC.⁹ F. nucleatum has been further studied now in oesophaggeal squamous cell carcinoma as well, with similar effects shown.¹⁰

Conclusion: Fusobacterium nucleatum is involved in the formation of colorectal cancer, metastasis, and chemotherapy resistance through modulating autophagy. By measuring levels of F. nucleatum in colorectal cancer patients, clinicians may be able to predict the patient’s chances of experiencing metastasis or chemoresistance, or if they may benefit from therapies such as immune checkpoint therapy or autophagy inhibitors. Future studies will have to be done to further explore the bacterium and if influencing different mechanistic steps could affect the treatment for CRC.

Works Cited:

1. Fong W, Li Q, Yu J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene. 2020;39(26):4925-4943. doi:10.1038/s41388-020-1341-1
2. Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell. 2017;170(3):548-563.e16. doi:10.1016/j.cell.2017.07.008
3. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16(12):713-732. doi:10.1038/s41575-019-0189-8
4. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-1480. doi:10.1016/S0140-6736(19)32319-0
5. Cheng Y, Ling Z, Li L. The Intestinal Microbiota and Colorectal Cancer. Front Immunol. 2020;11:615056. Published 2020 Nov 30. doi:10.3389/fimmu.2020.615056
6. Haruki K, Kosumi K, Hamada T, et al. Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer. J Pathol. 2020;250(4):397-408. doi:10.1002/path.5381
7.  Chen Y, Chen Y, Zhang J, et al. Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression [published correction appears in Theranostics. 2022 Jan 1;12(3):1333-1334]. Theranostics. 2020;10(1):323-339. Published 2020 Jan 1. doi:10.7150/thno.38870
8.  Kong C, Yan X, Zhu Y, et al. Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling. Cancer Res. 2021;81(17):4485-4498. doi:10.1158/0008-5472.CAN-21-0453
9. Gao Y, Bi D, Xie R, et al. Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade in colorectal cancer [published correction appears in Signal Transduct Target Ther. 2021 Dec 21;6(1):434]. Signal Transduct Target Ther. 2021;6(1):398. Published 2021 Nov 19. doi:10.1038/s41392-021-00795-x
10. Liu Y, Baba Y, Ishimoto T, et al. Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma. Br J Cancer. 2021;124(5):963-974. doi:10.1038/s41416-020-01198-5