Embracing cancer complexity: Hallmarks of systemic disease

Swanton, Charles; Bernard, Elsa; Abbosh, Chris; André, Fabrice; Auwerx, Johan; Balmain, Allan; Bar-Sagi, Dafna; Bernards, René; Bullman, Susan; DeGregori, James; Elliott, Catherine; Erez, Ayelet; Evan, Gerard; Febbraio, Mark A.; Hidalgo, Andrés; Jamal-Hanjani, Mariam; Joyce, Johanna A.; Kaiser, Matthew; Lamia, Katja; Locasale, Jason W.; Loi, Sherene; Malanchi, Ilaria; Merad, Miriam; Musgrave, Kathryn; Patel, Ketan J.; Quezada, Sergio; Wargo, Jennifer A.; Weeraratna, Ashani; White, Eileen; Winkler, Frank; Wood, John N.; Vousden, Karen H.; Hanahan, Douglas

doi:10.1016/j.cell.2024.02.009

Cited by 48 publications

(13 citation statements)

References 256 publications

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“…The occult transition could also represent a moment in time where malignancy is established by changes in the host that impact fitness of tumor cell phenotypes. These could be systemic in nature and may range from immune ageing, microbiome changes, obesity, injury and many others (Swanton et al 2024). The occult transition could also occur through oncogene driven differences in cell state plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, for any one clone that progresses to cancer, billions of transformed cells exist that will never successfully generate a tumor (Evans and DeGregori 2021). A major conceptual problem is that most of the disease process occurs over the course of several years, if not decades, and often requires cancer cell extrinsic events to promote progression (Gerstung et al 2020; Swanton et al 2024). Tumor volume doubling times (TVDT) observed during the visible phase and described by linear models, do not extrapolate to the initiating oncogenic event.…”

Section: Introductionmentioning

confidence: 99%

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Nonlinear progression during the occult transition establishes cancer lethality

Ginzel,

Chapman,

Sills

et al. 2024

Preprint

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Cancer screening is based upon a linear model of growth and invasion. Yet, early dissemination during the lengthy pre-diagnostic phase suggests that nonlinearity in growth can also occur. Therefore, we quantitatively traced the invisible and visible phases of tumorigenesis in the mammary gland for more than two-thousand tumors. Dynamic mathematical models of the invisible phase revealed an occult checkpoint resulting in nonlinear progression of transformed field cells. We found that expansile fields have increased dwell time at the occult checkpoint resulting in a large reservoir of image detectable precursors prior to invasion. In contrast, slowly proliferating lesions disseminate early and then transition rapidly through an occult checkpoint in a process we term nascent lethality. Our data illustrate how nonlinear growth across an occult checkpoint can account for a paradoxical increase in early-stage cancer detection without a dramatic reduction in metastatic burden.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nonlinear progression during the occult transition establishes cancer lethality

Ginzel,

Chapman,

Sills

et al. 2024

Preprint

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“…Oxidative stress and lipid peroxidation are major contributors to inflammation in the tumour. Inflammation is one of the hallmarks of cancer and is a key regulator of tumour immune infiltration [ 55 ]. Inflammatory molecules recruit immune cells in the tumour microenvironment [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term High-Fat Diet Limits the Protective Effect of Spontaneous Physical Activity on Mammary Carcinogenesis

Marlin,

Goepp,

Desiderio

et al. 2024

IJMS

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Breast cancer is influenced by factors such as diet, a sedentary lifestyle, obesity, and postmenopausal status, which are all linked to prolonged hormonal and inflammatory exposure. Physical activity offers protection against breast cancer by modulating hormones, immune responses, and oxidative defenses. This study aimed to assess how a prolonged high-fat diet (HFD) affects the effectiveness of physical activity in preventing and managing mammary tumorigenesis. Ovariectomised C57BL/6 mice were provided with an enriched environment to induce spontaneous physical activity while being fed HFD. After 44 days (short-term, ST HFD) or 88 days (long-term, LT HFD), syngenic EO771 cells were implanted into mammary glands, and tumour growth was monitored until sacrifice. Despite similar physical activity and food intake, the LT HFD group exhibited higher visceral adipose tissue mass and reduced skeletal muscle mass. In the tumour microenvironment, the LT HFD group showed decreased NK cells and TCD8+ cells, with a trend toward increased T regulatory cells, leading to a collapse of the T8/Treg ratio. Additionally, the LT HFD group displayed decreased tumour triglyceride content and altered enzyme activities indicative of oxidative stress. Prolonged exposure to HFD was associated with tumour growth despite elevated physical activity, promoting a tolerogenic tumour microenvironment. Future studies should explore inter-organ exchanges between tumour and tissues.

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“…Aging is associated with a failure to control inflammation in space and time (“inflamm-aging”) [ 44 ], and inflammation is also one of the hallmarks of cancer, likely acting through a combination of cell-autonomous effects (e.g., increased proliferation of cells leading to genomic and epigenomic instability) and non-cell-autonomous consequences (e.g., fibrosis, rarefaction of ECM components and local immunosuppression by myeloid-derived suppressor cells) [ 3 , 45 ]. For this reason, inflammation has a dual role in both aging and cancer, implying that suppression of inflammation may have a multipronged impact on the development of a large spectrum of age-associated disorders that includes both malignant and non-malignant diseases.…”

Section: Common Superior Causes Of Aging and Cancermentioning

confidence: 99%

Aging and cancer

Montégut,

López-Otín,

Kroemer

2024

Mol Cancer

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Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as ‘hallmarks’. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or ‘age-associated disease’. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.

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Embracing cancer complexity: Hallmarks of systemic disease

Cited by 48 publications

References 256 publications

Nonlinear progression during the occult transition establishes cancer lethality

Nonlinear progression during the occult transition establishes cancer lethality

Long-Term High-Fat Diet Limits the Protective Effect of Spontaneous Physical Activity on Mammary Carcinogenesis

Aging and cancer

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