Linoleic acid (LA) is an 18-carbon, polyunsaturated fatty acid (PUFA), which contains two cis double bonds. Because mammals cannot introduce a double bond at carbon atoms beyond C-9 in the fatty acid chain, linoleic acid (18:2 cis-Δ⁹,Δ¹²) and linolenic acid (18:3 cis-Δ⁹, Δ¹²,Δ¹⁵) are two essential fatty acids. LA possesses low melting temperature and provides fluidity to cell membranes. LA is mainly contained in plant oils, such as safflower oil and corn oil.

The effect of linoleic acid (LA) on health is still controversial. LA is one of the two essential fatty acids, which means dietary supplementation of LA is necessary for maintaining cell activity. Saturated fatty acids have been implicated in obesity, heart disease, diabetes, and cancer while PUFAs generally have a positive effect on health; however, a high ω-6/ω-3 ratio, which is associated with today’s Western diets, promotes the pathogenesis of many diseases, including cardiovascular disease, inflammatory diseases, and cancer. Several in vivo studies suggest that a high amount of ω-6 PUFA such as LA might enhance the incidence of some types of cancers via stimulation of epithelial cell proliferation. Experiments in animal models of mammary and colorectal carcinogenesis suggest that fatty acids promote tumor development; ω-6 PUFA generally stimulate tumor growth, while ω-3 fatty acids oppose this effect.

Other studies lead to opposite conclusions. The associations between monounsaturated fatty acids, trans fatty acids, PUFAs such as LA, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), or ω-3/ω-6 ratio, and colorectal cancer are not convincing. Contrary to data from animal experiments, human studies do not show an association of breast cancer risk with ω-6 PUFA intake. High LA and arachidonic acid (AA) concentrations have been observed in insulin resistance–associated diabetic complications and in some tumors, but these are multifactorial processes that include many lifestyle determinants. It is therefore questionable to involve only ω-6 fatty acids in their etiology.

The controversial roles of LA might be due to the possibility that different metabolic pathways result in opposite effects. ω-6 PUFAs play a significant role in inflammatory and/or immune responses by bioactive molecules including PGE2.

LA is integrated into cytoplasmic membrane and is metabolized to AA through γ-linolenic acid, and dihomo-γ-linolenic acid ( Arachidonic Acid-Pathway and Cancer). AA is stored as phospholipids in cytoplasmic membrane and serum, and is released by cleavage with phospholipase A2. AA is metabolized by cyclooxygenase-1 and cyclooxygenase-2 (COX-2) ( Cyclooxygenase-2 in Colorectal Cancer) to  prostaglandins (PGs), thromboxanes (TXs), and  Leukotrienes (LTs). COX-2 is an inducible enzyme of COXs, which is absent in normal cells. In contrast, COX-1 is a constitutive enzyme expressed ubiquitously. COX-2 expression is induced in carcinogenic processes in many malignancies, involving colorectal, esophageal, breast, lung, pancreatic, and bladder cancers. Induced COX-2 expression in epithelial cells and also in stromal cells provides PGE2 in the local tissues. PGE2 possesses immunosuppressive and pro-inflammatory effects. COX-2-dependent overproduction of PGE2 is hypothesized to be an important part of sustained proliferative and chronic inflammatory conditions in colorectal epithelium, which are closely associated with carcinogenesis ( Inflammation in Cancer). PGE2 also has a strong association with colorectal cancer progression by promoting cell survival, cell growth, migration, invasion, and angiogenesis ( Colon Cancer). The various biological effects exerted by PGE2 are through the G-protein coupled cytoplasmic membrane E-prostanoid receptors termed EP1 to EP4.

15-Lipoxygenase-1 (15-LOX-1) is known for its anti-inflammatory properties and has a profound influence on the development and progression of cancers. 15-LOXs belong to the structurally and functionally related nonheme iron dioxygenases family. 15-LOXs are responsible for oxidative metabolism of ω-6 PUFAs, such as LA and AA to eicosanoids. Two isoforms are known in 15-LOXs; 15-LOX-1 (leukocyte type) and 15-LOX-2 (epidermis type). Both isoforms are expressed in normal and tumor tissues in various combinations. Different from other LOXs, such as 5-LOX and 12-LOX, 15-LOXs, 15-LOX-1 is revealed also as an  apoptosis inducer in human cancers and inhibits cancer progression in several types of cancers, including colorectal, and breast cancers. By the contrary, reduction of 15-LOX-1 is correlated with the disease progression of breast and colon cancers.

For antitumor effects, 15-LOX-1 is closely associated with peroxisome proliferator-activated receptor γ (PPARγ) ( Peroxisome Proliferator-Activated Receptor and Cancer) activation. The oxidative metabolites of LA by 15-LOX-1 can function as endogenous activators and ligands of PPARγ. In particular, 9-hydroxyoctadecadienoic acid (9-HODE), 13-hydroxyoctadecadienoic acid (13-HODE), and 13-oxooctadecadienoic acid (13-OXO) have biological effects as a PPARγ ligand. PPARγ is originally identified to induce adipocyte differentiation. PPARγ is a nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARγ is dimerized with retinoic X receptor ( Retinoid Receptor Crosstalk in Cancer), and binds specific responsive element within promoter DNA sequence to regulate gene expression. PPARγ initiates transcription of genes associated with energy homeostasis, cell growth, and anti-/pro-inflammatory effect. PPARγ is activated by endogenous secreted prostaglandins and fatty acids. 15-Deoxy-δ(12,14)-prostaglandin J2 is a strong endogenous ligand of PPARγ. Decrease in PPARγ expression is associated with cancer metastasis. PPARγ plays a role in transcriptional regulation of cancer-related genes. Ligand activation of PPARγ in colorectal cancer cells attenuates colonic inflammation and causes a reduction growth via the induction of apoptosis. Conjugated LA (CLA), a strong ligand for PPARγ, has a substantial anticarcinogenic effect. Synthesized PPARγ ligands including troglitazone have been shown to be effective chemopreventive agents in a rat model of carcinogenesis and in AOM-induced colon cancer in mice. In in vitro transformation model, LA inhibits intestinal cell transformation. Inhibitory effect of PPARγ to cancer metastasis is also reported in several cancers, such as non-small cell lung cancer, colon cancer, thyroid cancer, and breast cancer. Downregulation of EGFR, TGF-α ( Epidermal Growth Factor Receptor Ligands), and upregulation of Bax, p21Waf-1 ( p21(WAF1/CIP1/SDI1)),  E-cadherin by PPARγ activation induce antiproliferative, proapoptotic, and prodifferentiation effects. These alterations of gene expressions provide LA-induced anticarcinogenic, antitumor, and antimetastatic effects on cancer cells.

The sequential alteration of concurrence of COX-2 upregulation and 15-LOX-1 downregulation is found in the adenoma–carcinoma transition in colorectal neoplasia ( Colorectal premalignant lesions). Low-grade adenomas express 15-LOX-1 but not COX-2; high-grade adenomas and early carcinomas show decreased 15-LOX-1 expression and induction of COX-2 expression; and advanced carcinomas express COX-2 but not 15-LOX-1. It possibly shows close association of the switching of LA-metabolizing pathways with colon cancer development and progression. In expression of 15-LOX-1, several conditions play an important role. Cytokines, such as IL-4 ( Interleukin-4) and IL-13, high ratio of ω-3/ω-6 fatty acids, and  nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac sulfone induce 15-LOX-1 expression and activation of PPARγ. Reciprocally, activated PPARγ represses COX-2 by inhibition of NFκB ( Nuclear Factor κB) and  AP-1. This negative regulation of COX-2 expression by PPARγ activation might be one of mechanisms of reverse expression between 15-LOX-1 and COX-2. Furthermore, promoter DNA methylation is responsible for silencing of 15-LOX-1 expression ( Epigenetic Gene Silencing). The epigenetic alteration might be a trigger to switch 15-LOX-1 repression and COX-2 upregulation along with malignant transformation and cancer progression in colon cancer.

Excess uptake of LA increases cancer metastasis by enhancing cell embedding into the target organs. LA-derived TXA2 accelerates platelets aggregation involving cancer cells. LA also affects cancer cell activity. Short-term treatment with LA induces apoptosis in cancer cells. In the nude mice peritoneal dissemination model, LA treatment inhibits formation of peritoneal metastasis. In contrast, cancer cells exposed to LA for a long term show quiescent condition in vitro and dormancy in transplanted animals. In these cells, decrease of EGFR, VEGF ( Vascular Endothelial Growth Factor), and increase of  BCL-2 are observed. Thus, LA might play a role in formation of cancer cell dormancy and delayed metastasis.

In summary, the effects of LA on human health are still not clearly figured out. As LA is an essential fatty acid, we cannot cease LA uptake. In further studies, it is important to make use of the beneficial side of the double-edged sword of LA for prevention and treatment of cancer.