Sugar (5) – Cancer:

Besides the link between sugar consumption and a shorter life (1), the link with cancer should get more attention.

It is well known that a large percentage of malignant tumors have an increase in anaerobic glycolysis, which means that they use glucose fermentation as fuel (2).

The great danger is that apart from feeding cancer, anaerobic glycolysis is highly inefficient for energy metabolism, since it produces only a couple of moles of ATP (energy) for each mole of glucose, when 38 moles would normally be produced in the complete aerobic oxidation of glucose. In other words, through this route, the cancer feeds at the same time that it wastes energy malnourishing the patient. Which may be the main reason why a large percentage die of cachexia (extreme weight loss) and the more sugar is consumed, the more this pathway is stimulated.

Even if the mitochondrial function in cancer seems to be robust (3), the idea that cancers use glucose fermentation as a main fuel even in the presence of oxygen, is widely accepted and may explains why manipulating the macronutrient ratio to use fat for fuel, seems to be useful in more than 80% of cancers; both for the enormous metabolic potential to delay cachexia, as well as for depriving the tumor of glucose, slowing its growth (more in the future blog “Ketosis, autophagy and cancer”).

Despite the fact that the vast majority of oncologists are far from considering feeding the patient in this way (or using any nutritional strategy), letting a cancer patient consume any type of sugar, in many cases could be like pouring gasoline on fire and in my humble opinion, a medical malpractice. However, this is completely overlooked in the medical community and a rarely discussed topic in general.

Let’s look at some signaling pathways that stimulate cancer, their relationship with sugar and the opinion of health professionals that strongly believe in this relationship.

The phosphoinositide-3-kinase pathway (PI3K) and the Mitogen-activated protein kinase (MAPK):

These are two of the main pathways that regulate most of the actions of insulin associated with metabolism and of course, great activators of the Growing Mode.

Despite being a fundamental part for the proper functioning of the body, as we insist every time we talk about the Growing Mode, it probably should be stimulated intermittently.

The western diet, and its nature rich in refined carbohydrates and sugar, is a very efficient way to activate this machinery continuously, which can lead to unwanted cell proliferation in healthy people and in most cancers, it may help them to grow more rapidly.

The MAPK pathway:

This pathway, which is directly related to insulin, activates transcription factors that mediate gene expression and the genes it activates, contribute to high cell growth and survival. For this reason, it is implicated in a variety of cancers, since its function itself leads to uncontrolled proliferation of cells, resistance to apoptosis (programmed cell death) and resistance to conventional therapies to treat cancer.

The PI3K pathway:

When PI3K is active, it converts the lipid PIP2 to its active form PIP3, which leads to the activation of the AKT kinase, which in turn promotes cell growth through the Growing Mode and reduces cell death through blocking the activity of the Foxo transcription factor, which is involved in cell metabolism and resistance to oxidative stress playing a fundamental role in healthy aging (721,722).

According to its discoverer, Dr Lewis Cantley, insulin is the best way to activate PI3K (4).

(TakeAway: The PI3K pathway stimulates growth and reduces programmed cell death (apoptosis), two fundamental processes for the development of cancer. Therefore, as with the MAPK pathway, its continuous stimulation may lead to the proliferation of malignant cells.)

Due to its growth-stimulating nature, the PI3K pathway is involved in several types of cancers, and its increased activity is related to resistance to treatments.

Since PI3K was discovered by Dr Lewis Cantley, to better understand this pathway and its relationship with sugar, let’s look at some summary excerpts from the scientific interviews with Dr Lewis Cantley and colleagues published in PubMed (5) and in the research journal Medicalxpress (6).

Dr. Cantley and colleagues observed that high levels of PI3K were correlated with malignant transformation of cells and they’ve shown that viruses that cause cancer in mice and chickens, often do so through this enzymatic activity.

As we’ve mentioned, Dr Cantley said that Insulin is the best way to activate PI3K (4), concluding that PI3K and PIP3 originally evolved to mediate insulin / IGF-1 signaling and control nutrient uptake, particularly glucose uptake in response to feeding.

According to a body of research accumulated by Dr. Cantley and his team at Weill Cornell Medicine, excess sugar helps many cancers grow faster and understanding how sugar feeds cancer, can lead to a new approach to the treatment (More in the future blog “Ketosis, autophagy and cancer”).

“As we learn more and more about cancer metabolism, we understand that individual cancers are addicted to particular things. In a lot of cancers, that’s insulin—and sugar.”

Dr Lewis Cantley

In cancer, the PI3K pathway changes at a high rate, providing tumors with an excess supply of glucose that drives their growth. So researchers in Dr. Cantley’s lab, including instructor in medicine Dr. Benjamin Hopkins, worked with colleagues to test the hypothesis that low carb diets would prevent spikes in blood sugar and could help a new PI3K inhibitor, do its job.

They showed that insulin spikes did indeed reactivate the pathway in tumors, counteracting the anticancer effect of the drug. But when the researchers severely restricted the mice’s carbohydrate intake, and put them on what’s known as a ketogenic diet, the tumors shrank (7).

“The evidence really suggests that if you have cancer, the sugar you are eating may be making it grow faster”

Dr Lewis Cantley

(TakeAway: Sugar seems to help various types of tumors to grow more rapidly through the stimulation of PI3K. For this reason, the use of an inhibitor of this pathway was experimented at the same time that insulin peaks were generated, leading to the reactivation of this pathway in tumors, even in the presence of the inhibitor. Conversely, carbohydrate restriction allowed the inhibitor to reduce the tumor growth.)

Breast cancer:

In an experiment done to study how sugar consumption could influence tumorigenesis in the mammary gland (8), researchers separated the mice into 4 feeding regimens:

Dextrose (control).
Fructose.
Dextrose and fructose.
Sucrose (sugar).

Compared to the group on the high-starch diet, those with sugar and fructose were much more likely to develop breast cancer, almost twice as much in the sugar group at 6 months. Also, the average tumor weight in the sugar group was 50 mg heavier than in the starch group, indicating that it also increased carcinoma proliferation.

“We determined that fructose derived from the sucrose was responsible for facilitating lung metastasis and 12-HETE production in breast tumors. Overall, our data suggested that dietary sugar induces 12-LOX signaling to increase risks of breast cancer development and metastasis”

“Our findings suggested that dietary sucrose/fructose induced 12-LOX/12-HETE production in breast tumor cells in vivo is a possible signaling pathway responsible for sugar-promoted tumor growth in mice. How dietary sucrose/fructose induces 12-HETE and whether it is a direct or an indirect effect remains in question”

Obesity and cancer:

There is absolutely no doubt that weight gain has grown in parallel with the consumption of vegetable seed oils and sugar.

Obesity is the most obvious dysfunction of the consequences of the continuous activation of the Growing Mode to the naked eye. But sadly, it is not just a cosmetic issue.

(Note: The fact that we link obesity to cancer in the sugar chapter, does not necessarily mean that obesity is an exclusive consequence of sugar consumption)

The association between obesity and cancer is clear (9,10,11) and is more closely related to certain types of cancers. These include endometrial, colon, kidney, gallbladder, esophageal adenocarcinoma, breast cancer in postmenopausal women (12,13,14,15) and gastrointestinal tract tumors (16,17).

The ability of adipose tissue to generate factors that increase cellular susceptibility to cancer initiation or progression has been supported in a variety of studies on different forms of this disease.

Some of these factors, which we will list below, act through specific receptors that, in turn, regulate the key pathways in the control of cell viability, proliferation, migration and death.

Hormonal changes.
High levels of insulin and IGF-1.
High expression of fatty acid synthase.
High levels of ceruloplasmin.
Resistance to leptin.
Low levels of adiponectin.
Abnormal levels of IL-6 and TNF-α.
Chronic inflammation.

Although it is not necessary to know in detail each one, we should understand that all these factors related to both high sugar consumption and obesity, are also related to cancer. So, let’s see a short description of each of these associations.

Hormonal changes:

The increase in the expression of aromatase by leptin (18,19) and estrogens produced in adipose tissue (20) influence the development of cancers sensitive to these hormones.

These steroids can promote carcinogenesis and be enhanced with the use of oral contraceptives, hormone replacement therapy, or even pregnancy (20).

(Note: The hormonal changes mentioned, are directly proportional to the amount of adipose tissue.)

Insulin and IGF-1:

Insulin-like growth factor 1 or IGF-1, is another great activator of the Growing Mode and inhibitor of the Recycling Mode, which together with insulin, take a large part of the role in anabolic processes.

Insulin resistance together with the stimulation of IGF-1 in the liver (21), are a characteristic of obesity.

Insulin is highly active in adipose tissue and both high levels of this hormone (22,23,24), as well as IGF (25), are known factors in cancer risk.

More studies:

Insulin resistance associated with obesity may be a symptom of a dysfunction of the insulin / IGF-1 axis (22,26).
Insulin sensitivity is related to the development of cancer and other diseases related to aging (27).
Activation of insulin and IGF-1 receptors has been shown to activate tumor growth (28,29).
Insulin resistance associated with obesity leads to an increase in free IGF-1 levels in the postprandial state (after eating), while in subjects sensitive to this hormone with little body fat, a reduction is observed (30).
High levels of insulin could deregulate IGF-1 signaling (31), resulting in higher levels of free IGF.
The risk of colorectal cancer in men has been associated with higher levels of circulating IGF-1 (32).
The upregulation of insulin and IGF-1R (IGF-1 receptor), are present in cancer (33,34).
Upon activation of insulin and IGF-1R, the intracellular protein Ras stimulates the MAPK pathway, which also plays a vital role in cell proliferation and inhibition of apoptosis. (29,35).
There is a strong relationship between fasting insulin levels and postmenopausal cancer risk (36).

(TakeAway: High levels of insulin and IGF -1, which are a hallmark of obesity, are great initiators of the Growing Mode.

As two highly anabolic hormones, the alteration in their regulation is related to the onset and development of various types of cancers, tumor cell proliferation and inhibition of apoptosis.)

Fatty acid synthase:

This is a multifunctional enzyme that catalyzes the synthesis of fatty acids (fat generation). When it is inhibited, it induces a rapid decrease in fat stores in mice (37) and on the contrary, a higher expression of the FASN gene (the gene that expresses it) is related to the accumulation of visceral fat (38).

There is a relationship between increased expression of fatty acid synthase and a worse prognosis in prostate, colon, breast, gastrointestinal and ovarian tumors (39,40,41,42), while on the contrary, its inhibition has shown efficacy in therapy against cancer (43,44).

Ceruloplasmin:

Angiogenesis is the formation of new blood vessels, which can benefit tumor growth.

Ceruloplasmin, which is highly concentrated in the adipose tissue of obese individuals (45), is involved in angiogenesis, which is why it could promote various types of cancers.

Leptin:

Leptin is a specific hormone of adipocytes (fat cells), involved in the regulation of food intake, metabolism, body weight, and appetite suppression (46).

Although this hormone inhibits appetite, the typical resistance to leptin that accompanies obesity does not allow this suppressive effect (47). The more adipose tissue, the greater the amount of leptin and the greater the amount of leptin, the greater the desensitization of the receptors (resistance to the hormone), which closes the vicious circle with greater secretion.

More studies:

The incidence of various types of cancers increases with elevated levels of circulating leptin (48,49).
Leptin receptor expression has been identified in various types of cancers (50,51).
High leptin levels are associated with an increased risk of colon (48) and breast (52,49) cancer, being higher in postmenopausal women with greater waist circumference and higher leptin concentrations.
Leptin is a stimulator of cell proliferation and tumor growth (53,54,55,56,57).
Leptin is a promoter for cyclin D1 (54), a major contributor to cell cycle progression and suppression of apoptosis (programmed cell death) in ovarian cancer cells (53).
The activation of PI3K and MAPK by leptin also promotes angiogenesis, contributing to tumor growth (54).
Additional carcinogenic actions of leptin include increased aromatase expression, leading to improved pro-estrogenic pathways, estradiol production, and estrogen-α receptor signaling (18,19), factors that are of particular importance in estrogen-sensitive cancers.

(TakeAway: High levels of this hormone, which are proportional to the amount of adipose tissue in leptin resistant individuals, are related to the stimulation of angiogenesis and inhibition of apoptosis, an increased risk of colon cancer, breast cancer, ovarian cancer, and of estrogen-sensitive cancers.)

More adipokines:

Apart from leptin, the adipokines that we will mention here are adiponectin, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), since the adipose tissue growth in obesity leads to increased plasma levels of the inflammatory factors TNF-α and IL-6, with a reduction in the production of the beneficial adiponectin (58,59,60).

Adiponectin:

Adiponectin is a peptide hormone that has antiangiogenic properties (reduction of new blood vessel formation) in vitro (50) and has a physiological role in glucose metabolism, insulin sensitivity (61) and in the stimulation of fatty acid oxidation (62).

The positive effects of this hormone are reduced in overweight patients, since unlike other adipokines, adiponectin concentrations are significantly lower in obese individuals (63).

More studies:

The dual action of positive regulation of AMPK (Recycling Mode) and inhibition of Akt (Growing Mode), has been considered an important characteristic of the effects mediated by the antiproliferative and pro-apoptotic effect (inducer of programmed cell death) of adiponectin in malignant cells (64).
There is an association between circulating adiponectin levels, cancer risk, and disease severity (65,66,67,68,69).
Adiponectin inhibits colorectal cancer cell growth in vitro (probably negatively regulating mTOR through AMPK phosphorylation) (70).
Low levels of adiponectin contribute to insulin resistance (71).
By increasing insulin sensitivity (61,62), adiponectin prevents cancer growth.

(TakeAway: This hormone, found at significantly lower levels in obese people, improves insulin sensitivity, stimulates lipid oxidation, inhibits cell proliferation in cancer, induces apoptosis (programmed cell death), and reduces angiogenesis (formation of new blood vessels that benefit the tumor).)

TNF-α:

Tumor necrosis factor alpha (TNF-α) is expressed and secreted in adipose tissue, that is, the more fat, the more TNF-α (59,72). For this reason, obesity and high levels of TNF-α are related.

TNF-α is a cytokine that mediates immunity. For example, in the face of an infection, TNF-α will have its own pro-inflammatory response, as well as through the regulation of other inflammatory mediators such as interleukin 6 (IL-6), which we will see below.

When the immune system is working properly, TNF-α protects the body. However, alterations in TNF-α levels can cause serious dysfunctions, such as, for example, the correlation with the prevalence of colorectal adenomas (72), which are typical lesions that precede the development of colorectal cancer.

Functionally, TNF-α regulates other adipokines and can induce cancer cell survival, promoting oncogenesis.

(TakeAway: TNF-α protects the body, but high levels such as those seen in obesity, may collaborate in carcinogenesis.)

IL-6:

Like TNF-α, interleukin 6 (IL-6) is produced in response to infections and injuries, but continuous and unregulated synthesis has a pathological effect on chronic inflammation and autoimmunity.

More studies:

Plasma levels of IL-6 in patients with morbid obesity are significantly higher (73,60,74).
Elevated IL-6 levels are related to the incidence of various types of cancers (48,49).
High levels of IL-6 are observed in ovarian and hepatocellular carcinoma (75).
The IL-6 receptor (IL-6R) appears to activate an essential antiapoptotic and proliferative mechanism in tumor cells (76,77).
IL-6 stimulation of the PI3K / Akt (Growing Mode) pathway leads to the expression of cyclin D1 (78), as well as the modulation of other intracellular proteins that support tumor growth.
IL-6 also inhibits dendritic immune cell differentiation and promotes immune tolerance, reducing T cell vigilance and cytotoxicity (79).
Insulin can promote the release of IL-6 into the circulation and induce the expression of the TNF-α gene within adipose tissue (80).

(TakeAway: IL-6 is protective, but its dysregulation is pathological. This dysregulation is observed in obese patients and is related to ovarian and hepatocellular carcinoma, the inhibition of apoptosis, the stimulation of cell proliferation and a reduction in the immune system’s vigilance capacity.)

Chronic inflammation:

Although we have seen inflammation markers separately, here we are going to reflect on some more studies that we could not leave out.

So far, we have looked at the action of TNF-α and IL-6 separately and here, we will add C-reactive protein in a summary of relevant studies on the relationship between chronic inflammation, cancer and obesity.

(Note: C-reactive protein is produced in the liver in response to inflammation, which together with TNFa and IL-6 among others, are part of the inflammatory response cocktail.)

More studies:

Chronic inflammation is associated with several non-infectious physiological conditions, including obesity (81,82,83,84).
Obesity is related to increased levels of IL-6, TNF-α, and C-reactive protein (85,72).
Chronic local and systemic inflammation, favor tumor initiation and progression (86,87,88).
In obese individuals, the net balance shifts toward a pro-inflammatory state, promoting an oncogenic environment (89).
Both TNF-α and IL-6 are produced by fat cells (59,85) and macrophages, which typically accumulate in tissues with higher adiposity (90,91).
A medium conditioned with visceral adipocytes (fat cells) promoted an increase in the formation of inflammatory cells, which in turn, secreted greater amounts of adipogenic factors (fat generation), generating a vicious circle.

Taken together, these results imply a substantial pro-inflammatory environment associated with visceral adipocytes, which would favor carcinogenesis in an obese host (92).

Correlations have been made between local chronic inflammatory conditions, such as inflammatory bowel disease, and an increased risk of developing cancers (93), while systemic inflammation has been correlated with a higher prevalence of colorectal adenomas.

(TakeAway: Adipose tissue secretes a variety of chemicals that have marked effects on metabolism and whose dysregulation can lead to chronic inflammation.

Chronic inflammation is directly related to obesity and the onset and progression of various types of cancers.)

(Conclusion: In my humble opinion, I don’t think sugar is carcinogenic by itself, but the evidence suggests that high consumption of sugar has the potential to make some types of cancer grow faster. Also, the link between sugar and obesity…and obesity and cancer, is clear.)