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Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination.

ABSTRACT: Heterogeneity within tumour cell populations is commonly observed in most cancers. However, its impact on metastatic dissemination, one of the primary determinants of the disease prognosis, remains poorly understood. Working with a simplified numerical model of tumour spheroids, we investigated the impact of mechanical heterogeneity on the onset of tumour invasion into surrounding tissues. Our work establishes a positive link between tumour heterogeneity and metastatic dissemination, and recapitulates a number of invasion patterns identified in vivo, such as multicellular finger-like protrusions. Two complementary mechanisms are at play in heterogeneous tumours. A small proportion of stronger cells are able to initiate and lead the escape of cells, while collective effects in the bulk of the tumour provide the coordination required to sustain the invasive process through multicellular streaming. This suggests that the multicellular dynamics observed during metastasis is a generic feature of mechanically heterogeneous cell populations and might rely on a limited and generic set of attributes.

SUBMITTER: Hallou A

PROVIDER: S-EPMC5579073 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination.

Hallou Adrien A Jennings Joel J Kabla Alexandre J AJ

Royal Society open science 20170823 8

Heterogeneity within tumour cell populations is commonly observed in most cancers. However, its impact on metastatic dissemination, one of the primary determinants of the disease prognosis, remains poorly understood. Working with a simplified numerical model of tumour spheroids, we investigated the impact of mechanical heterogeneity on the onset of tumour invasion into surrounding tissues. Our work establishes a positive link between tumour heterogeneity and metastatic dissemination, and recapit ...[more]

PMID: 28878958

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Project description:Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are important for the secretion, activation, and function of mature TGFβ, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP3 in the distinct processes involved in cancer metastasis. By using three human tumor cell lines of different tissue origin (epidermoid HEp-3 and prostate PC-3 carcinomas and HT-1080 fibrosarcoma) and several metastasis models conducted in both mammalian and avian settings, we show that LTBP3 is involved in the early dissemination of primary cancer cells, namely in the intravasation step of the metastatic cascade. Knockdown of LTBP3 in all tested cell lines led to significant inhibition of tumor cell intravasation, but did not affect primary tumor growth. LTBP3 was dispensable in the late steps of carcinoma cell metastasis that follow tumor cell intravasation, including vascular arrest, extravasation, and tissue colonization. However, LTBP3 depletion diminished the angiogenesis-inducing potential of HEp-3 cells in vivo, which was restorable by exogenous delivery of LTBP3 protein. A similar compensatory approach rescued the dampened intravasation of LTBP3-deficient HEp-3 cells, suggesting that LTBP3 regulates the induction of the intravasation-supporting angiogenic vasculature within developing primary tumors. Using our recently developed microtumor model, we confirmed that LTBP3 loss resulted in the development of intratumoral vessels with an abnormal microarchitecture incompatible with efficient intravasation of HEp-3 carcinoma cells. Collectively, these findings demonstrate that LTBP3 represents a novel oncotarget that has distinctive functions in the regulation of angiogenesis-dependent tumor cell intravasation, a critical process during early cancer dissemination. Our experimental data are also consistent with the survival prognostic value of LTBP3 expression in early-stage head and neck squamous cell carcinomas, further indicating a specific role for LTBP3 in cancer progression toward metastatic disease.

Dataset Information

Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination.

Publications

Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination.

Similar Datasets

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