Acanthosis nigricans most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation.
In the benign form of acanthosis nigricans, the factor is probably insulin or an insulinlike growth factor (IGF) that incites the epidermal cell propagation. Other proposed mediators include other tyrosine kinase receptors (epidermal growth factor receptor [EGFR] or fibroblast growth factor receptor [FGFR]).
At high concentrations, insulin may exert potent proliferative effects via high-affinity binding to IGF-1 receptors. In addition, free IGF-1 levels may be elevated in obese patients with hyperinsulinemia, leading to accelerated cell growth and differentiation. 
Familial and syndromic forms of acanthosis nigricans have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin-resistance syndromes and fibroblast growth factor defects.
Insulin-resistance syndromes include those with mutations in the insulin receptors (ie, leprechaunism, Rabson-Mendenhall syndrome), peroxisome proliferator-activated receptor gamma (ie, type 1 diabetes with acanthosis nigricans and hypertension), 1-acylglycerol-3-phosphate O-acyl transferase-2 or seipin (Berardinelli-Seip syndrome), lamin A/C (Dunnigan syndrome), and Alstrom syndrome gene. Fibroblast growth factor defects include activating mutations inFGFR2 (Beare-Stevenson syndrome), FGFR3 (Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, severe achondroplasia with developmental delay, and acanthosis nigricans [SADDAN]). Familial cases of acanthosis nigricans with no other syndromic findings have also been linked to FGFR mutations. [3, 4]
Perspiration or friction may also play a contributory role, as suggested by the predilection of acanthosis nigricans for body folds.
In malignant acanthosis nigricans, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)–alpha is structurally similar to epidermal growth factor and is a likely candidate. TGF-alpha and epidermal growth factor have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within acanthosis nigricans lesions. Reports of urine and serum TGF-alpha levels normalizing after surgical tumor removal exist, with subsequent regression of skin lesions. 
Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely due to activation of IGF receptors. [6, 7] Agents such as palifermin (recombinant keratinocyte growth factor used to decrease mucositis with chemotherapy and stem cell transplantation) have reportedly produced transient but dramatic acanthosis nigricans–like lesions, presumably due to activation of the FGFR.