Tumor suppressor genes in the tumor microenvironment

Sep 23, 2026

Uploaded by Aurelia

Tumor suppressor genes (TSGs) are widely viewed as regulators that curb tumor development mainly through cancer cell–autonomous mechanisms, yet the tumor microenvironment (TME) is increasingly recognized as a decisive driver of tumorigenesis. Evidence from clinical expression analyses and mouse models with TSG deletion in the TME supports their functional role across multiple TME cell types. Using TP53 and PTEN, this Perspective proposes both proactive and reactive models linked to the timing of initiating events, and calls for integrated cancer-treatment strategies targeting both tumor cells and the TME.

LanguageEnglish

CategoryHealthcare

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Pages7

Reading Time18 min

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Introduction

Alteration of TSG expression in the tumor microenvironment

TP53

© 2025 . Published by The Company of Biologists | Disease Models & Mechanisms (2025) 18, dmm052049 . doi:10 . 1242/dmm.052049 PERSPECTIVE Tumor suppressor genes in the tumor microenvironment Bahareh Tabanifar1, Hannah Lau2,3 and Kanaga Sabapathy3,* ABSTRACT | Tumor suppressor genes (TSGs) are thought to suppress tumor development primarily via cancer cell-autonomous mechanisms. However, the tumor microenvironment (TME) also significantly influences tumorigenesis. In this context, a role for TSGs in the various cell types of the TME in regulating tumor growth is emerging. Indeed, expression analyses of TSGs in clinical samples, along with data from mouse models in which TSGs were deleted selectively in the TME, indicate a functional role for them in tumor development. In this Perspective, using TP53 and PTEN as examples, we posit that TSGs play a significant role in cells of the TME in regulating tumor development, and postulate both a ‘pro-active’ and ‘reactive’ model for their contribution to tumor growth, dependent on the temporal sequence of initiating events. Finally, we discuss the need to consider a 2-in-1 cancer-treatment strategy to improve the efficacy of clearance of cancer cells and the cancer-promoting TME.
KEY WORDS: Fibroblasts, TP53, PTEN, Tumor microenvironment, Tumor suppressors | | --- | | Introduction
Oncogene activation and tumor suppressor gene (TSG; Box 1) inactivation are considered to be the primary causal events in the transformation of normal cells en route to malignancy (Solomon et al., 2010; Hanahan and Weinberg, 2011) . Alterations in their expression are often sufficient to promote cellular proliferation or inhibit apoptosis, eventually resulting in cellular transformation, thereby underscoring their cell-autonomous roles in the tumorigenic process (Hanahan and Weinberg, 2011; Zhu et al., 2015) . Not surprisingly, most cancer genome sequencing efforts have focused on cataloguing such alterations, and molecular therapies target these tumor-cell-specific alterations (Guo et al., 2014) . However, it is increasingly clear that the tumor microenvironment (TME; Box 1) that surrounds tumor cells (Anderson and Simon, 2020) impacts on tumor initiation, progression, metastasis and therapy resistance (Valkenburg et al., 2018; de Visserand Joyce, 2023) . Recent studies have also alluded to a significant role for adipocytes and myofibroblasts in prognosticating overall survival in breast cancers (Li et al., 2021; Lau et al., 2023) . Interestingly, modifications in stromal gene expression, especially of TSGs, have been postulated to affect neighboring tumor cells (Moinfar et al., 2000; Scherz-Shouval et al., 2014; Wu et al., 2022) . For instance, loss of tumor suppressor functions in the stroma (Box 1) | 1Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore 168583 . 2Department of Physiology, National University of Singapore, Singapore 117558 . 3School of Biological Sciences, Nanyang Technological University, Singapore 637551 . *Author for correspondence ([kanaga.sabapathy@ntu.edu.sg](kanaga.sabapathy@ntu.edu.sg)) K.S. , 0000-0002-4346-7386 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0](https://creativecommons.org/licenses/by/4.0)), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. may either directly affect tumor cell properties or, alternatively, lead to pre-malignant changes in the adjacent epithelial cells (Bhowmick et al., 2004; Wu et al., 2022), although these effects could be celltype specific. Whether the expression and functions of oncogenesand TSGs in the stromal cells (Box 1) ofthe TME play a significant role in the tumorigenic process has not been unequivocally established. We focus here on the role of two commonly mutated TSGs in the TME, i.e. TP53 and PTEN

FAQs

How do tumor suppressor genes (TSGs) influence tumor development according to this Perspective?

TSGs are proposed to regulate tumor growth not only through cancer-cell-autonomous effects but also through functional roles in multiple TME cell types. Clinical expression data and TME-specific deletion studies in mice support this broader influence.

Which TSGs are used as key examples in the Perspective, and why?

TP53 and PTEN are used as examples because evidence from clinical samples and animal models indicates significant contribution of these genes within the TME to tumor development.

What models are proposed for how TSGs contribute to tumor growth?

The Perspective proposes a proactive and a reactive model for TSG contribution to tumor growth. The relative relevance of these models is dependent on the temporal sequence of initiating events.

Sep 23, 2026

Uploaded by Aurelia