Review of the androgen receptors and gastrointestinal cancer

Gastrointestinal (GI) cancer is the prevalent cause of global cancer deaths, and its effective treatments are lacking. This common malignancy can be identified through hematomas or black stools. It includes the cancers of digestive system, i.e., esophagus, stomach, liver, pancreas and colon. It is surgically removed followed by the conservative management. The incidence of GI cancer in men is 2–3 times higher compared to women. This higher prevalence in men is because of the involvement of sex steroid hormones via androgen receptor. The clinical case studies in men are continuously being conducted, however there are unanswered questions regarding the therapeutics. In this review, future therapeutic strategies of GI cancer and gastrointestinal stromal tumor (GIST) are being encompassed.

Gastrointestinal cancer; Gastrointestinal stromal tumor; Sex steroid hormone; Men’s health

[1] Mehrabadi S, Velayati M, Zafari N, Hassanian SM, Mobarhan MG, Ferns G, et al. Growth-hormone-releasing hormone as a prognostic biomarker and therapeutic target in gastrointestinal cancer. Current Cancer Drug Targets. 2023; 23: 346–353.

[2] Obri MS, Nimri F, Kamran W, Nimri R, Pompa R, Zuchelli T. Gastrointestinal stromal tumor presenting as food impaction and pseudo-achalasia. ACG Case Reports Journal. 2023; 10: e01116.

[3] Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, et al. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Therapeutic Advances in Medical Oncology. 2023; 15: 17588359231192388.

[4] Kumar V, Gala D, Wonders C, Marowa S, Forlemu A, Gayam V, et al. Non-islet cell tumor hypoglycemia associated with gastrointestinal stromal tumor: case report and review of the literature. Archive of Clinical Cases. 2023; 10: 50–54.

[5] Ağagündüz D, Cocozza E, Cemali Ö, Bayazıt AD, Nanì MF, Cerqua I, et al. Understanding the role of the gut microbiome in gastrointestinal cancer: a review. Frontiers in Pharmacology. 2023; 14: 1130562.

[6] Jardim SR, de Souza LMP, de Souza HSP. The rise of gastrointestinal cancers as a global phenomenon: unhealthy behavior or progress? International Journal of Environmental Research and Public Health. 2023; 20: 3640.

[7] Sabbatino E, Tutino V, Licitra F, Di Donato M, Castoria G, Migliaccio A, et al. Role of the androgen receptor in gender-related cancers. Endocrines. 2023; 4: 407–426.

[8] Martínez-Rojo E, Berumen LC, García-Alcocer G, Escobar-Cabrera J. The role of androgens and androgen receptor in human bladder cancer. Biomolecules. 2021; 11: 594.

[9] Banibakhsh A, Sidhu D, Khan S, Haime H, Foster PA. Sex steroid metabolism and action in colon health and disease. The Journal of Steroid Biochemistry and Molecular Biology. 2023; 233: 106371.

[10] Abdel-Hamid NM, Al-Quzweny RM. Prevalence of hepatocellular carcinoma in men and the contribution of androgen and its receptor in pathogenesis and therapy. Current Molecular Pharmacology. 2023; 16: 559–563.

[11] Abdalla TSA, Pieper L, Kist M, Thomaschewski M, Klinkhammer-Schalke M, Zeissig SR, et al. Gastrointestinal stromal tumors of the upper GI tract: population-based analysis of epidemiology, treatment and outcome based on data from the German Clinical Cancer Registry Group. Journal of Cancer Research and Clinical Oncology. 2023; 149: 7461–7469.

[12] Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020; 159: 335–349.e15.

[13] Busada JT, Peterson KN, Khadka S, Xu X, Oakley RH, Cook DN, et al. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology. 2021; 161: 637–652.e4.

[14] Loomans-Kropp HA, Umar A. Analysis of body mass index in early and middle adulthood and estimated risk of gastrointestinal cancer. JAMA Network Open. 2023; 6: e2310002.

[15] Long E, Beales ILP. The role of obesity in oesophageal cancer development. Therapeutic Advances in Gastroenterology. 2014; 7: 247–268.

[16] Sheikh M, Roshandel G, McCormack V, Malekzadeh R. Current status and future prospects for esophageal cancer. Cancers. 2023; 15: 765.

[17] Liu C, Ma Y, Qin Q, Wang P, Luo Y, Xu P, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thoracic Cancer. 2023; 14: 3–11.

[18] Wang Z, Sun S, Li K, Huang C, Liu X, Zhang G, et al. Feasibility analysis of combined surgery for esophageal cancer. World Journal of Surgical Oncology. 2023; 21: 41.

[19] López MJ, Carbajal J, Alfaro AL, Saravia LG, Zanabria D, Araujo JM, et al. Characteristics of gastric cancer around the world. Critical Reviews in Oncology/Hematology. 2023; 181: 103841.

[20] Huang C, Liu H, Hu Y, Sun Y, Su X, Cao H, et al. Laparoscopic vs open distal gastrectomy for locally advanced gastric cancer. JAMA Surgery. 2022; 157: 9.

[21] Inaguma G, Shibasaki S, Nakauchi M, Serizawa A, Nakamura K, Akimoto S, et al. Muscle mass ratio in male gastric cancer patients as an independent predictor of postoperative complications after minimally invasive distal gastrectomy. Surgical Endoscopy. 2023; 37: 989–998.

[22] Zhao L, Jin L, Petrick JL, Zeng H, Wang F, Tang L, et al. Specific botanical groups of fruit and vegetable consumption and liver cancer and chronic liver disease mortality: a prospective cohort study. The American Journal of Clinical Nutrition. 2023; 117: 278–285.

[23] Lugari S, Baldelli E, Lonardo A. Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms. Metabolism and Target Organ Damage. 2023; 3: 5.

[24] Fujitani H, Eguchi H, Kochi Y, Arai T, Muramatsu M, Okazaki Y. Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study. European Journal of Cancer Prevention. 2023; 32: 286–297.

[25] Hussain AM, Lafta RK. Cancer trends in Iraq 2000–2016. Oman Medical Journal. 2021; 36: e219.

[26] Baraibar I, Ros J, Saoudi N, Salvà F, García A, Castells MR, et al. Sex and gender perspectives in colorectal cancer. ESMO Open. 2023; 8: 101204.

[27] Kumar A, Chinnathambi S, Kumar M, Pandian GN. Food intake and colorectal cancer. Nutrition and Cancer. 2023; 75: 1710–1742.

[28] Liao H, Li C, Ai Y, Kou Y. Gut microbiome is more stable in males than in females during the development of colorectal cancer. Journal of Applied Microbiology. 2021; 131: 435–448.

[29] Phoenix JT, Budreika A, Kostlan RJ, Hwang JH, Fanning SW, Kregel S. Editorial: Hormone resistance in cancer. Frontiers in Endocrinology. 2023; 14: 1272932.

[30] McAllister M, Constâncio V, Patek S, Gan HWG, Bailey P, Wheadon H, et al. Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer. The Prostate. 2020; 80: 1353–1364.

[31] Dean AE, Reichardt F, Anakk S. Sex differences feed into nuclear receptor signaling along the digestive tract. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease. 2021; 1867: 166211.

[32] Sanders KM, Drumm BT, Cobine CA, Baker SA. Ca2+ dynamics in interstitial cells: foundational mechanisms for the motor patterns in the gastrointestinal tract. Physiological Reviews. 2024; 104: 329–398.

[33] Ma C, Li B, Silverman D, Ding X, Li A, Xiao C, et al. Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. Nature Neuroscience. 2024; 27: 249–258.

[34] Palsson OS, Tack J, Drossman DA, Le Nevé B, Quinquis L, Hassouna R, et al. Worldwide population prevalence and impact of sub‐diagnostic gastrointestinal symptoms. Alimentary Pharmacology & Therapeutics. 2024; 59: 852–864.

[35] Zhu W, Oteiza PI. Proanthocyanidins at the gastrointestinal tract: mechanisms involved in their capacity to mitigate obesity-associated metabolic disorders. Critical Reviews in Food Science and Nutrition. 2024; 64: 220–240.

[36] Saker Z, Rizk M, Nabha S. Androgen receptor-dependent mechanisms mediating therapy resistance in prostate cancer. Therapy Resistance in Prostate Cancer. 2024; 73: 57–84.

[37] Viehweger F, Dum D, Menz A, Uhlig R, Hinsch A, Höflmayer D, et al. Androgen receptor (AR) is frequently found in human cancers and inversely linked to patient outcome in breast and renal cell carcinomas. Cancer Research. 2023; 83: 5563.

[38] Chew DCH, Yim CHH, Ali RAR, El-Omar EM. Epidemiology, microbiome, and risk factors involved in carcinogenesis of esophagus, gastric, and intestine. In Jankowski JAZ (ed.) Gastrointestinal oncology: a critical multidisciplinary team approach 2e (pp. 2–22). 2nd edn. Wiley-Blackwell: Hoboken. 2024.

[39] Hu C, Fang D, Xu H, Wang Q, Xia H. The androgen receptor expression and association with patient’s survival in different cancers. Genomics. 2020; 112: 1926–1940.

[40] Cotter KA, Gallon J, Uebersax N, Rubin P, Meyer KD, Piscuoglio S, et al. Mapping of m6a and its regulatory targets in prostate cancer reveals a METTL3-low induction of therapy resistance. Molecular Cancer Research. 2021; 19: 1398–1411.

[41] Blay JY, Kang YK, Nishida T, von Mehren M. Gastrointestinal stromal tumours. Nature Reviews Disease Primers. 2021; 7: 22.

[42] Zhang H, Liu Q. Prognostic indicators for gastrointestinal stromal tumors: a review. Translational Oncology. 2020; 13: 100812.

[43] Gheorghe G, Bacalbasa N, Ceobanu G, Ilie M, Enache V, Constantinescu G, et al. Gastrointestinal stromal tumors—a mini review. Journal of Personalized Medicine. 2021; 11: 694.

[44] Husain NE, Osman IM, Khalid A, Satir AA, Stoehr R, Agaimy A. Clinicopathological, immunohistochemical, molecular-genetic and risk profiles of gastrointestinal stromal tumors in a cohort of Sudanese patients. African Health Sciences. 2023; 23: 444–458.

[45] Enodien B, Hendie D, Müller T, Taha-Mehlitz S, Frey DM, Taha A. Gastrointestinal stromal tumor (GIST): a remarkable case report and literature review. Cureus. 2023; 15: e35931.

[46] Yorke J, Brenu SG, Awoonor-Williams R, Tabiri S, Seidu AS, Yamoah FA, et al. A gist on an obscure neoplasm in Ghana: gastrointestinal stromal tumours. BMC Research Notes. 2023; 16: 318.

[47] Raut CP, Espat NJ, Maki RG, Araujo DM, Trent J, Williams TF, et al. Efficacy and tolerability of 5-year adjuvant imatinib treatment for patients with resected intermediate- or high-risk primary gastrointestinal stromal tumor. JAMA Oncology. 2018; 4: e184060.

[48] Jeong ISD, Abiri P, Cai J, Yim C, Powell L. A case of non-cirrhotic hyperammonemic encephalopathy in a patient with metastatic gastrointestinal stromal tumor. Cureus. 2023; 15: e37541.

[49] Kanda T, Naito T, Wakai A, Iwafuchi Y, Hirota S, Ajioka Y. Late recurrence of low-risk gastrointestinal stromal tumor of jejunum diagnosed 30 years after tumor resection: a case report and literature review. Oncology Letters. 2023; 25: 50.

[50] Calise AC, Leuthner Z, Griffith Z. Rare presentation of a gastrointestinal stromal tumor encapsulating the spleen: a case report. Cureus. 2023; 15: e37125.

[51] Joensuu H, Wardelmann E, Eriksson M, Reichardt A, Hall KS, Schütte J, et al. KIT and PDGFRA mutations and survival of gastrointestinal stromal tumor patients treated with adjuvant imatinib in a randomized trial. Clinical Cancer Research. 2023; 29: 3313–3319.

[52] Wagner AJ, Severson PL, Shields AF, Patnaik A, Chugh R, Tinoco G, et al. Association of combination of conformation-specific KIT inhibitors with clinical benefit in patients with refractory gastrointestinal stromal tumors. JAMA Oncology. 2021; 7: 1343.

[53] Yeap JH, Tan PG, Leow VM, Ramasamy U. Large locally advanced duodenal gastrointestinal stromal tumor (GIST) successfully managed by combined use of neoadjuvant imatinib and surgical resection. SAS Journal of Surgery. 2023; 9: 18–20.

[54] Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015; 350: 1079–1084.

[55] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018; 359: 97–103.

[56] Dahiya D, Nigam PS. Biotherapy using probiotics as therapeutic agents to restore the gut microbiota to relieve gastrointestinal tract inflammation, IBD, IBS and prevent induction of cancer. International Journal of Molecular Sciences. 2023; 24: 5748.

[57] Ağagündüz D, Cocozza E, Cemali Ö, Bayazıt AD, Nanì MF, Cerqua I, et al. Understanding the role of the gut microbiome in gastrointestinal cancer: a review. Frontiers in Pharmacology. 2023; 24: 1130562.

[58] Ren L, Zhang T, Zhang J. Recent advances in dietary androgen receptor inhibitors. To be published in Medicinal Research Reviews. 2024. [Preprint].

[59] Guo C, Zhang L, Zhao M, Ai Y, Liao W, Wan L, et al. Targeting lipid metabolism with natural products: a novel strategy for gastrointestinal cancer therapy. Phytotherapy Research. 2023; 37: 2036–2050.

[60] Rashwan HH, Taher AM, Hassan HA, Awaji AA, Kiriacos CJ, Assal RA, et al. Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies. Pathology, Research and Practice. 2024; 256: 155223.

[61] Kubra KT, Akhter MS, Apperley K, Barabutis N. Growth hormone-releasing hormone antagonist JV-1-36 suppresses reactive oxygen species generation in A549 lung cancer cells. Endocrines 2022; 3: 813–820.