Upsala Journal of Medical Sciences. 2012; 117: 217–224 REVIEW ARTICLE Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors ANNIKA JÖGI1,2, MARICA VAAPIL1,2, MARTIN JOHANSSON1 & SVEN PÅHLMAN1,2 1Department of Laboratory Medicine, Center for Molecular Pathology, Skåne University Hospital Malmö, Malmö, Sweden, and 2CREATE Health, Lund University, Malmö, Sweden Abstract The differentiation stage of tumors is a central aspect in the histopathological classiﬁcation of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied. Key words: Breast cancer, dedifferentiation, differentiation, EMT, hypoxia, neuroblastoma, prostate cancer, skin cancer, tumor-initiating cells, tumor stem cells Introduction The biological meaning of the term differentiation denotes the developmental process whereby cells grad- ually acquire the capacity for a more specialized func- tion by change of phenotype. While developmental biologists generally view this process as unidirectional, observations in the context of cancer show that the differentiation process can reverse and that cells can dedifferentiate. Despite the fact that classical tumor diagnostics based on surgical pathology and histology for decades have used tumor cell differentiation status as one important aspect to score, evaluate, and com- municate tumor aggressiveness, overall experimental tumor biology has over the years not focused on the differentiation processes, but rather studied molecular pathways leading to growth, migration, and cell death. However, the rapid and recent development of stem cell as well as tumor stem cell research have galvanized the study of the differentiation processes in cancer, which has provided insights into the cellular and molecular biological underpinnings of cancer-driven mechanisms leading to changes in the degree of cellular differentiation or dedifferentiation. In this contribution we discuss the impact of the tumor cell differentiation stage on tumor behavior and the use of this important concept in surgical pathology. We further summarize knowledge gained from exploring the differentiation and dedifferentiation processes in two tumor forms, neuroblastoma and breast cancer. Correspondence: Sven Påhlman, Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital Malmö, Entrance 78, S-20502 Malmö, Sweden. Fax: +46 40336073. E-mail: sven.pahlman@med.lu.se (Received 13 October 2011; accepted 17 January 2012) ISSN 0300-9734 print/ISSN 2000-1967 online 2012 Informa Healthcare DOI: 10.3109/03009734.2012.659294