IGF-1 LR3 and cancer risks: what the research says

The question "can IGF-1 LR3 cause cancer" is one of the most common in the sporting community and at the same time one of the most complicated. There are no direct studies in humans, so the answer has to be assembled from several sources: the biology of the IGF-1 receptor, epidemiological work, "natural experiments" such as Laron syndrome and acromegaly, and the warnings for registered drugs. The editors have sorted out this data.

Why IGF-1 is linked to oncology at all

IGF-1 acts mainly through the type 1 IGF-1 receptor (IGF-1R) — a tyrosine kinase close in structure to the insulin receptor. After the receptor is activated, two key intracellular cascades are triggered: PI3K-Akt-mTOR, which suppresses apoptosis and stimulates protein synthesis, and RAS-MAPK, which stimulates cell division. It is precisely these pathways that are responsible for the anabolic effects for the sake of which the substance is used by athletes.

The problem is that these same cascades are actively used by tumor cells. Michael Pollak's review in Nature Reviews Cancer (2008) described how insulin and IGF signaling promotes the survival, proliferation and resistance of tumors to therapy. In many types of cancer, increased expression of IGF-1R or hybrid receptors is found.

It is important to distinguish initiation and progression. There is no convincing evidence that IGF-1 by itself turns a normal cell into a cancerous one. However, it can create an environment in which cells with already existing mutations survive and multiply more easily. The growth factor acts as "fertilizer", not as "seed".

That is precisely why oncologists studied IGF-1R for decades as a target for antitumor drugs. The clinical results of receptor blockers turned out to be modest, but the very fact of such interest shows how seriously the scientific community regards this signaling pathway in the context of cancer.

Epidemiology: IGF-1 level and cancer risk

From the end of the 1990s, large cohort studies began to compare the level of IGF-1 in the blood of healthy people with the subsequent development of cancer. The meta-analysis by Renehan et al., published in The Lancet in 2004, showed that higher concentrations of IGF-1 were associated with a moderately increased risk of prostate cancer and breast cancer in premenopausal women.

Subsequently, analyses of large cohorts, in particular the European EPIC, and pooled data for prostate cancer generally confirmed the association for individual sites. For some other types of cancer the link was weak or ambiguous.

These data have important limitations. First, they concern natural fluctuations of IGF-1 within the physiological range, not pharmacological administration. Second, an association does not prove causality: high IGF-1 may be a marker of other factors, for example nutrition or height. Third, the increase in relative risk was moderate.

However, it is precisely these limitations that make the data alarming for the situation with LR3. If even relatively small natural differences in IGF-1 level are associated with a change in cancer risk, then the consequences of administering an analogue that bypasses the natural control of binding proteins are impossible to predict.

Natural experiments: Laron and acromegaly

One of the most interesting sources of data was people with Laron syndrome — a hereditary insensitivity to growth hormone in which the level of IGF-1 is very low. Guevara-Aguirre et al. (2011) described an Ecuadorian cohort with such a mutation: among them, over decades of observation, cancer was practically not recorded, whereas in their relatives without the mutation it occurred with the expected frequency.

The same work also described a very low incidence of type 2 diabetes. The authors linked these observations to reduced activity of the GH/IGF-1 signaling pathways. Although the group is small and specific, the result became a strong argument in favor of the role of IGF-1 in oncogenesis.

The opposite "experiment" is acromegaly, in which a pituitary tumor produces an excess of growth hormone, and hence of IGF-1. In patients with acromegaly an increased incidence of colon polyps has long been discussed, and clinical guidelines call for colonoscopic screening. Regarding the overall cancer risk the data are contradictory, but the topic remains a subject of attention for endocrinologists.

None of these examples is a direct model of the use of IGF-1 LR3. But together they form a consistent picture: the stronger the signaling of the GH/IGF-1 axis, the more grounds for oncological vigilance.

What is known about IGF-1 LR3 and registered analogues

About IGF-1 LR3 itself there is no oncological data in humans: the drug never underwent clinical trials. It is known only that in cell culture it stimulates growth more potently than native IGF-1, precisely because of reduced binding to IGFBP. This property is used in biotechnology, where cells are needed to grow faster.

The binding proteins in the body also perform a protective function: IGFBP-3, in particular, demonstrated antiproliferative effects in a number of experimental works. An analogue that "bypasses" this control could theoretically prolong and enhance the effect on tissues, including on cells with precancerous changes.

The only widely available registered analogue, mecasermin, gives a useful hint. In 2019 the FDA added to its prescribing information a warning about cases of malignant neoplasms in children and adults who received the drug, and a contraindication in active or suspected neoplasms. Note: this concerns a medicinal product in physiologically grounded doses under the supervision of a doctor.

So, there is no direct evidence that LR3 causes cancer. But there is also no evidence of safety, and all the indirect data point in one direction. For a molecule with no medical indication whatsoever, such uncertainty weighs far more than for a drug that saves children with severe growth deficiency.

How to assess the risk in practice

The editors do not and cannot give recommendations regarding the use of IGF-1 LR3. But for people who already have such experience or are considering it, it is useful to know which factors theoretically increase oncological vigilance.

• A family history of cancer, especially of the prostate, breast, colon.
• Known precancerous conditions: intestinal polyps, dysplastic nevi, thyroid nodules.
• Age: with the years the incidence of hidden microscopic tumors increases.
• Combination with other substances that enhance growth: growth hormone, insulin, anabolic steroids.
• Duration of exposure: oncological effects, if they exist, may appear years later.

For people with any of these factors it is especially important to undergo age-appropriate screening examinations and to honestly inform the doctor about the use of the drugs. The doctor will not "pass judgment", but this information changes the plan of examination.

It should also be remembered that there are risks of a poor-quality product: on the illegal market, under the name LR3, other proteins, solutions with impurities or outright placebo may be sold. This makes any risk assessment even less predictable.

Editorial conclusions

IGF-1 is one of the key signals of cell survival and division, and its link with oncology is supported by biological, epidemiological and clinical observations. People with genetically low IGF-1 hardly develop cancer, and a warning about neoplasms has appeared in the prescribing information of registered IGF-1.

For IGF-1 LR3 there is no direct data, but its main property — bypassing the control of binding proteins — makes the theoretical risks higher, not lower.

The absence of evidence of harm in this case cannot be interpreted as evidence of safety: no one has simply conducted the relevant studies.

We also recommend reading "The history of the discovery of IGF-1 LR3", "IGF-1 LR3 and carbohydrate metabolism" and "Melanotan II and cancer risks: what the research says".

References

1. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8(12):915–928.
2. Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363(9418):1346–1353.
3. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13.
4. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23(6):824–854.
5. Francis GL, Ross M, Ballard FJ, et al. Novel recombinant fusion protein analogues of insulin-like growth factor (IGF)-I indicate the relative importance of IGF-binding protein and receptor binding for enhanced biological potency. J Mol Endocrinol. 1992;8(3):213–223.
6. Increlex (mecasermin) injection. Prescribing information. U.S. Food and Drug Administration.
7. Holt RIG, Sönksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol. 2008;154(3):542–556.