How does a mole form?

Also known as a nevus, a mole is a benign and colored skin growth. While the size of moles varies, their average diameter is estimated to be 6 mm. Some are flat and smooth, while others are raised, rough, or covered in hair. Contrary to initial assumptions, moles are not necessarily brown or black: there are also blue or gray ones. In any case, moles should be monitored to prevent melanomas.

Moles form when melanocytes, the cells in the basal layer responsible for the production of melanin, proliferate excessively and in a localized manner.

Under normal circumstances, melanocytes are evenly distributed throughout the skin. However, in moles, they cluster to form denser and visible structures. This anomaly can be influenced by genetic factors, with some individuals expressing more genes that regulate the growth and differentiation of melanocytes. Some studies have even shown that a mutation in the BRAF gene is associated with a higher risk of melanoma and nevi. Hormonal factors or repeated and prolonged exposure to the sun, whose UVB rays stimulate the activity of melanocytes, can also be a cause. The biological events leading to excessive proliferation of melanocytes are still under study, but the following steps are assumed.

• Step 1 : Reduction in the expression of E-cadherin.

  E-cadherin is a protein that ensures the adhesion of melanocytes to keratinocytes. Its reduction leads to the detachment of melanocytes and promotes their grouping. This phenomenon can be induced by the hepatocyte growth factor, a molecule produced by the dermal fibroblasts. This factor stimulates the migration of melanocytes and reduces the expression of E-cadherin, thus facilitating their detachment. Exposure to UV rays also plays a role by increasing the production of endothelin-1 by keratinocytes, which reinforces the decrease in E-cadherin and promotes the dispersion of melanocytes. Other mechanisms could be involved, including an epigenetic modification: an as yet unknown enzyme could methylate DNA and inhibit the production of E-cadherin. TGF-β, a factor involved in cellular regulation and response to external signals, could also contribute to this process.

• Step 2 : Loss of communicating junctions.

  Communicating junctions, or gap junctions, allow skin cells to exchange essential chemical and electrical signals for their coordination. When E-cadherin is reduced, these junctions between melanocytes and keratinocytes become disorganized, disrupting intercellular communication. Melanocytes then escape the regulatory signals sent by keratinocytes. Although the exact consequences of this loss of communication remain uncertain, it could disrupt the distribution of melanocytes and promote their aggregation.

• Step 3 : Dendrite retraction.

  Normally, melanocytes have dendrites, long cellular extensions that allow them to transfer melanin to surrounding keratinocytes. However, during the formation of moles, these extensions retract, thus reducing interactions with the epidermis. Some researchers hypothesize that this retraction could be controlled by Rac1, a protein belonging to the Rho GTPases family, involved in the regulation of the cellular cytoskeleton and the dynamics of cellular extensions. The exact mechanism is still poorly understood, but certain physical or environmental factors, such as changes in tissue tension, could trigger this phenomenon.

• Step 4 : Induction of proliferation.

  Once melanocytes are uncoupled from keratinocytes and stripped of their dendrites, they can enter a phase of proliferation. This cellular multiplication is thought to be stimulated by various mitogenic factors, molecules that promote cell division. These factors can be produced by the dermal fibroblasts, such as the basic fibroblast growth factor, or by keratinocytes, which notably release the stem cell growth factor (SCF) and leukotrienes. Among these signals, the SCF linked to the keratinocyte membrane appears to play a key role because, once it is released through enzymatic cleavage, it stimulates the proliferation of melanocytes.

• Step 5 : Migration.

  Following their proliferation, melanocytes must disperse and reposition themselves to prevent excessive accumulation. Normally, they are spaced five to eight keratinocytes apart along the basal membrane, and their anchorage relies on integrins, adhesion proteins, such as the laminin receptor α6β1. Another potential player in this repositioning is the Notch signaling pathway, present on cell membranes and can be activated depending on the melanocyte/keratinocyte ratio, thus ensuring cellular balance. When this process fails, melanocytes can migrate abnormally and cause the appearance of a nevus.

• Step 6 : Homeostasis.

  Once the melanocytes are positioned, a cellular rebalancing must occur to stabilize their organization. This process relies on the reactivation of E-cadherin, which restores adhesion between cells and allows intercellular communication. Thanks to this restoration of communicating junctions, melanocytes cease to migrate and regain balance with the surrounding keratinocytes.