We investigated the status of the PI 3‐kinase/AKT/PTEN signaling pathway in a series of 117 head and neck squamous cell carcinomas (HNSCC) in a search for molecular alterations in genes/proteins with potential prognostic value. For this purpose, PIK3CA and AKT2 gene amplification was assessed by multiplex and Quantitative Real‐Time PCR. Protein expression of AKT, p‐AKT, p110α and PTEN was determined by Western blot. PTEN allelic loss was evaluated by microsatellite analysis. PTEN‐exon 5 was screened for point mutations by PCR‐SSCP. Homozygous deletions were determined by multiplex PCR. PIK3CA gene was amplified in 43/117 (37%) fresh tumor samples, a frequency that did not differ from that found in archival premalignant tissues: 15/38 (39%); 12/40 (30%) fresh tumors harbored AKT2 gene amplification. AKT was found activated in 6/36 (17%) fresh tumor samples, when compared to their normal tissue counterparts. Of these 6 cases, 1 showed p110α overexpression and 5 displayed PTEN protein downregulation. Neither allelic loss (found in 11/77 informative cases) nor point mutations or homozygous deletions accounted for the reduced PTEN protein expression observed in our tumor series. The histologically normal mucosa of 4 patients displayed some of the molecular alterations analyzed. Dysregulation of the PI 3‐K/AKT/PTEN pathway might contribute to early HNSCC tumorigenesis and might constitute a potential clinical target. Overall, 17/36 (47%) cases showed at least 1 of the molecular alterations studied here, which makes the PI 3‐kinase‐initiated signaling pathway one of the most frequently altered in HNSCC.

Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long‐term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell‐of‐origin, which are the normal cells that acquire the first cancer‐promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell‐of‐origin. Both the cell‐of‐origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS‐CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC‐associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell‐of‐origin models, the properties of the OS‐CSC and its niche, and potential new therapies able to target OS‐CSCs.