Abstract
Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.
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M.F. and T.S. conceptualized the overall focus and content of the article. S.S. contributed substantially to discussion of the content. M.F. wrote the article with input from all authors. All authors reviewed and edited the manuscript before submission.
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Glossary
- Anaplastic tumours
-
Undifferentiated tumours with no apparent direction for differentiation.
- Bi-lineage progenitors
-
Progenitor cells that can differentiate into two distinct types of differentiated cell.
- Cribriform
-
A term that derives from the Latin term cribrum and describes a histological appearance characterized by multiple punched-out lumens bridged by tumour cells, sometimes referred to as a Swiss cheese-like pattern.
- Endoluminal tumours
-
Tumours that develop from the inner surface of tract organs.
- Fundic polyps
-
Benign neoplasms that develop mainly in the healthy gastric epithelium without H. pylori infection.
- Gastritis
-
An inflammatory condition of the gastric epithelium, predominantly caused by infection with Helicobacter pylori.
- Goblet cell
-
A type of epithelial cell that produces mucins and secretes them into the tract lumen.
- Histotype
-
Nomenclature to categorize a given tissue based on its histological attributes and nearly similar to a histological subtype.
- Licensing pioneer factor
-
Transcription factor that can bind to closed chromatin and facilitate further association with other transcription factors.
- Neuroendocrine carcinoma
-
A histological variant of carcinoma with poor differentiation and expression of neuroendocrine markers.
- Oncofetal markers
-
Marker proteins expressed in tumours and also in fetal tissues.
- Sessile serrated lesion
-
A type of colon polyp characterized by a serrated ‘saw-like’ surface, L-shaped distortion of the crypt bottom, predominance in the proximal colon, frequent BRAF mutation and CpG island hypermethylation.
- Signet ring cell carcinoma
-
A type of carcinoma that frequently occurs in the stomach that is characterized by ring-like tumour cells with abundant intracellular mucin and an eccentrically located nucleus, which are typically discohesive.
- Traditional serrated adenoma
-
A subtype of serrated lesions characterized by slit-like serrations, eosinophilic cytoplasm, pencillated nuclei, ectopic crypts along the crypt axis, predominance in the distal colon and recurrent RSPO gene fusion.
- Tubular adenoma
-
The most predominant type of colon cancer precursor typically initiated by APC loss of function and characterized by largely conserved normal crypt structures, crypt elongation, increased number of glands and variable degrees of dysplasia.
- Ulcerative colitis
-
An inflammatory bowel disease that causes idiopathic chronic inflammation in the rectal and colonic mucosa.
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Fujii, M., Sekine, S. & Sato, T. Decoding the basis of histological variation in human cancer. Nat Rev Cancer 24, 141–158 (2024). https://doi.org/10.1038/s41568-023-00648-5
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DOI: https://doi.org/10.1038/s41568-023-00648-5
