Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

Sep 22, 2026

Malignancy arises from genetic and/or epigenetic alterations that deregulate growth and enable invasion and metastasis. Current therapies can remove tumors, yet many malignancies recur with reduced susceptibility, linked to dormancy of surviving malignant cells. The mechanisms controlling entry into and exit from dormancy remain insufficiently defined, and the cell of origin is emphasized as a key driver. The review links differentiated-cell long-term proliferative stimulation to cancer stem cell emergence and late metastases.

LanguageEnglish

CategoryHealthcare

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Pages9

Reading Time23 min

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Introduction

Cell of origin: differentiated versus stem cells

TYPE Mini Review PUBLISHED 10 April 2024 DOI 10.3389/fonc.2024.1369907 OPEN ACCESS EDITED BY Daitoku Sakamuro, Augusta University, United States REVIEWED BY Luis Fernando Me´ ndez Lo´pez, Autonomous University of Nuevo Leo´n, Mexico *CORRESPONDENCE Helge Waldum [helge.waldum@ntnu. no](helge.waldum@ntnu. no) RECEIVED 26 January 2024 ACCEPTED 25 March 2024 PUBLISHED 10 April 2024 CITATION Waldum H and Slupphaug G (2024) Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases. Front. Oncol. 14:1369907 . doi: 10.3389/fonc.2024.1369907 COPYRIGHT © 2024 Waldum and Slupphaug. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases Helge Waldum* and Geir Slupphaug Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway Malignancy manifests itself by deregulated growth and the ability to invade surrounding tissues or metastasize to other organs. These properties are due to genetic and/or epigenetic changes, most often mutations. Many aspects of carcinogenesis are known, but the cell of origin has been insufﬁciently focused on, which is unfortunate since the regulation of its growth is essential to understand the carcinogenic process and guide treatment. Similarly, the concept of cancer stem cells as cells having the ability to stop proliferation and rest in a state of dormancy and being resistant to cytotoxic drugs before“waking up” and become a highly malignant tumor recurrence, is not fully understood. Some tumors may recur after decades, a phenomenon probably also connected to cancer stem cells. The present review shows that many of these questions are related to the cell of origin as differentiated cells being longterm stimulated to proliferation. KEYWORDS bone metastases, cancer cell of origin, cell adherence, differentiated versus stem cell, direct versus indirect stimulation, dormancy, late metastases 1 Introduction Malignancy is characterized by deregulated growth and the ability to invade surrounding tissues or metastasize to other organs. Current treatments for malignant tumors include surgery, irradiation, and cytotoxic drugs, often leading to the apparently complete removal of tumors. Unfortunately, many such tumors recur with reduced treatment susceptibility, even after initially effective interventions. Such recurrence often leads to the death of the patient and has been explained by the dormancy of malignant cells that initially survived the cytotoxic treatment (1) . The mechanisms governing entry into and emergence from dormancy remain inadequately understood (1) . The present review aims to elucidate this phenomenon with a particular emphasis on the cells of origin of cancers. Frontiers in Oncology 01 [frontiersin.org](frontiersin.org) 2 Cell of origin: differentiated versus stem cells Our points of view are mainly based upon long-term experience in gastroenterology including gastric physiology and pathology. During the late seventies and early eighties, it became evident that the gastric hormone gastrin stimulated the enterochromafﬁn-like (ECL) cell to proliferation and neoplasia in rodents and humans (2–5), and before the identiﬁcation of the ECL cell, Azzopardi and Pollock (6) focused on argentafﬁn (neuroendocrine cell marker) cel

FAQs

Why is identifying the cell of origin important for cancer treatment?

Because regulation of the cell of origin is essential to understand the carcinogenic process and to guide treatment more effectively.

How do cancer stem cells relate to dormancy and late metastases?

Cancer stem cells can stop proliferation, remain dormant, and resist cytotoxic drugs before “waking up,” contributing to highly malignant tumor recurrence and late metastases.

What does the review say about differentiated cells and long-term stimulation?

The review argues that some long-term stimulation of differentiated cells can be linked to questions about the emergence of cancer stem cells and development of late, highly malignant disease.

Sep 22, 2026

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