Therapeutic strategy in colorectal cancer based on Traditional Chinese and Western Medicine: from the lipid metabolism perspective

Colorectal cancer (CRC) is a major cause of morbidity and mortality and is closely associated with lipid metabolism, of which fatty acid metabolism, the release of fat factors and the abnormal level of blood lipids are all important pathogenic mechanisms. With the increasing awareness of lipid metabolism, advances in lipid-regulating therapy have made it possible for anti-tumor effect in CRC. However, there are still many research gaps and limitations. Given the complexity and uncertainty of targeted lipidregulating therapy for CRC, traditional Chinese medicine (TCM) may have a leg up when it comes to the theory of “holistic concept” and “treatment based on syndrome differentiation”. Meanwhile, proper dietary direction, healthy lifestyles, and normal serum lipid levels contribute directly to the prognosis of CRC patients. Key words—Lipid metabolism, Colorectal cancer, Lipidregulating therapy, Treatment strategies, Traditional Chinese medicine Highlights—Lipid metabolism is closely associated with colorectal carcinogenesis and development, which emerges as a potential therapeutic target gradually. Besides, in view of the complexity and uncertainty of targeted lipid-regulating therapy for colorectal cancer, traditional Chinese medicine might provide novel insights, explanations and directions to the lipid-regulating therapy in colorectal cancer. INTRODUCTION Colorectal cancer (CRC) is one of the most common malignant tumors with the third morbidity and fourth mortality in the global world [1]. The etiology of CRC is unknown but closely related to the environment, heredity, lifestyle and diet [2], as well as metabolic diseases such as obesity, hyperlipidemia, hypertension and diabetes [3]. Lipid metabolism is emerging as a potential therapeutic target gradually. Besides, TCM might provide novel insights, explanations and directions to the lipid-regulating therapy. Therefore, this study reviewed and investigated the mechanism of lipid metabolism and TCM comment. LIPID METABOLIC ALTERATIONS OF TUMOR CELLS Tumor metabolism is more exuberant than that of normal cells, with obvious differences in energy metabolism such as sugar, lipid, nucleic acid and protein. Since Weinberg put forward the anaerobic glycolysis of tumor cells, researches on tumor metabolism have been deepened. Lipids play an essential role in the cellular structure and function, involved in biofilm formation, Qian-Qian Niu is with Department of Oncology, First Teaching Hospital of Tianjin University of TCM, Tianjin, 300385, China. Yuan-Hong Zhao is with Department of Oncology, First Teaching Hospital of Tianjin University of TCM, Tianjin, 300385, China. E-mail: yuanhongzh98@163.com (Corresponding author). signaling and energy supply. Lipid metabolic alterations are the key feature of tumor cells, which is mainly characterized by the enhancement of de novo synthesized fatty acid to promote early tumor progression mediated by various transcriptional factors and lipid metabolic enzymes [4], also closely related to tumor cellular growth, proliferation, apoptosis, migration, inflammatory response and antineoplastic drug resistance. CRC AND ADIPOSE TISSUE Adipose tissue formed by the accumulation of adipocytes stores energy for the body, and as the important endocrine organ, which regulates immunity and autophagy [5] by secreting a large number of adipokines and cytokines such as tumor necrosis factor (TNF α), interleukin (IL)-6 and IL-8. Moreover, long-standing inflammation of adipose tissue also induces colorectal carcinogenesis and progression [6, 7]. CRC AND THE LEVEL OF BLOOD LIPID The elevated level of free fatty acid (FFA) in serum may induce oxidative stress, lipo-toxicity or hypertriglyceridemia [5]. FFA4 is highly expressed in colorectal cancer cell lines and animal models with unclear mechanism [8]. Epidemiological studies have found that the level of serum lipid metabolism was closely linked to CRC. Elevated high-density lipoprotein (HDL) level was the protective factor for CRC [9], while total cholesterol (TCHO) was the risk factor [10]. Additionally, triglyceride (TC) is currently uncertain [5] and may be associated with the occurrence of colorectal adenomas [11]. LIPID LOWERING THERAPY OF CRC Decreasing origins of lipids Limiting external lipid uptake ω-3 and ω-6 polyunsaturated fatty acids are essential fatty acids that can only be obtained from food. The former is mainly ingested from vegetable oil, walnut and green vegetables, while the latter is more common in animal fats [5]. Findings have shown that diets rich in ω-6 fatty acids promoted inflammation, cardiovascular disease and cancer, while ω-3 fatty acids exerted anti-inflammatory actions, inhibition of IL-1β, IL-6, and TNF-α, and diminished the risk of CRC [12]. Recent studies also found that the incidence of CRC in Asia was on the rise, which might be caused by excessive intake of animal fat [1]. Overall, it is very vital to keep a balanced diet and optimize the intake ratio of essential fatty acids. Overexpression of CD36 induces tumor metastasis, a transmembrane channel protein [13] that promotes the absorption of lipids in the extracellular 2 Drug Combination Therapy environment, which also develops the anti-tumor therapy and cure. Limiting de novo synthesized fatty acid The augmented levels of fatty acid synthesis enzymes are common in malignancy, including fatty acid synthase (FASN), acetyl-CoA synthetase (ACS), ATP citrate lyase (ACLY), fatty acid CoA ligase (ACSL) and acetyl CoA carboxylase (ACC) [4]. FASN is the most extensively studied therapeutic target at present. Several kinds of FASN inhibitors, such as cyanin, C75 and orlistat, have entered the clinical trials [14]. And TVB3166 [15], the new FASN inhibitor, also showed strong anti-tumor activity in CRC cells. Furthermore, inhibition of the synthesis of these lipids might be a therapeutic strategy in the treatment of antiangiogenic therapy resistance. In addition, studies have shown that human breast cancer and colon cancer cells progressed after sunitinib exhibited increasing fatty acid synthesis, and FASN inhibitors might mitigate this growth and metastasis [16]. ACSL4 is upregulated in some colon adenocarcinomas, and inhibitors of ACSL4 attenuates the proliferation of tumor cells [17]. Sterol regulatory element binding proteins (SREBPs) are the key regulators of cellular lipid homeostasis, with high expression in CRC cells. Hence, their further proliferation may be limited by blocking the transcription SREBPs 4. Additionally, liver X-activated receptor (LXR) activates fatty acid synthesis by inducing SREBP-1c. And SR9243, an LXR inverse agonist, could inhibit lipids synthesis and promote cell apoptosis [18]. Inhibition of fatty acid desaturation Stearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids (FAs) for further synthesis of glycerophospholipid, sphingolipid and other lipids. Researches have demonstrated that SCD was a risk factor for poor prognosis and progression of patients with CRC [19]. And betulinic acid (BetA), an inhibitor of SCD, causes apoptosis in CRC cells