Hypoxia and the extracellular matrix: drivers of tumour metastasis

Gilkes, Daniele M.; Semenza, Gregg L.; Wirtz, Denis

doi:10.1038/nrc3726

Cited by 1,180 publications

(1,036 citation statements)

References 192 publications

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“…Overall, these results demonstrate that the 3D hypoxic hydrogel regulates sarcoma matrix remodeling through hypoxic induction of HIF-1α expression. These results are consistent with various sarcoma studies in vivo (15,24,25), suggesting that the HI hydrogels are an appropriate 3D model with the necessary biological attributes to study sarcoma cell invasion and migration.…”

Section: Resultssupporting

confidence: 79%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

117

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Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O 2 ) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O 2 depletion. Here, we report the impact of hypoxic O 2 gradients on sarcoma cell invasion and migration. O 2 gradient measurements showed that large sarcoma mouse tumors (>300 mm 3 ) contain a severely hypoxic core [≤0.1% partial pressure of O 2 (pO 2 )] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO 2 ). To analyze tumor invasion, we used O 2 -controllable hydrogels to recreate the physiopathological O 2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O 2 gradient accurately, we examined individual sarcoma cells embedded in the O 2 -controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O 2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O 2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O 2 -controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.hydrogel | sarcoma | hypoxia | gradients | migration S oft tissue sarcomas are a heterogeneous group of malignant cancers derived from transformed cells of mesenchymal origin (1, 2). Approximately 13,000 new cases per year are diagnosed in the United States alone, with 25-50% of patients developing recurrent and metastatic disease (3-5). Current clinical data suggest that undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive sarcoma subtypes, which frequently results in lethal pulmonary metastases that are insensitive to radio/chemotherapy. It has recently become apparent that sarcoma progression and metastasis are regulated by microenvironmental cues, such as extracellular matrix (ECM) remodeling, stiffness modulation, cellto-cell/matrix interactions, signaling factors, and spatial gradients (6-8). Of all these factors, low intratumoral oxygen (O 2 ; hypoxia) is most dramatically associated with pulmonary metastasis and poor clinical outcomes (9, 10).Intratumoral hypoxia occurs when the partial pressure of O 2 (pO 2 ) falls below 5%, and it is a commonly observed feature of many sarcomas. Regional hypoxia develops as rapidly growing tumors outstrip their blood supply and as a consequence of aberrant tumor angiogenesis. As a result, O 2 gradients develop throughout the growing tumor. Tumor hypoxia promotes c...

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Section: Resultssupporting

confidence: 79%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

117

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“…lung) with lower CCN2 expression) showed opposite effects on the same parameters. Elevated CCN2 expression in stromal cells is associated with the desmoplastic reaction and general stromal effects on tumor cells, likely reflecting the known association with hypoxic microenvironments, cancer associated fibroblasts that modulate angiogenesis, tumor cell migration and metastatic behavior (Rachfal et al 2004;Gilkes et al 2014;Shiga et al 2015;Kim et al 2014). The fact that these can be suppressed in some cancers and stimulated in others suggests a complex scenario of associated interacting factors.…”

Section: Ccn2 (Ctgf)mentioning

confidence: 99%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

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“…The microenvironment of the free abdominal space is hypoxic and deficient in glucose [35] . The cancer cells, which are seeded in the peritoneal cavity, must survive, proliferate, and migrate in this environment.…”

Section: Cell Survival In the Microenvironment Of The Peritoneal Cavitymentioning

confidence: 99%

“…Therefore, anoikis resistance is required for cells surviving in the peritoneal cavity and anchorage-independent growth [36] . HIF1α is reportedly involved in PD in GC, colorectal cancer, and pancreatic cancer [35,37] . HIF1α is induced by hypoxia and functions as a master regulator of cellular and systemic homeostatic responses to hypoxia by activating the transcription of many genes, including those involved in glucose metabolism and other adaptations to hypoxia [38][39][40] .…”

Section: Cell Survival In the Microenvironment Of The Peritoneal Cavitymentioning

confidence: 99%

Molecular mechanism of peritoneal dissemination in gastric cancer

Hu¹,

Ito²,

Yanagihara³

et al. 2018

JCMT

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Peritoneal dissemination (PD) is the most common cause of metastasis in gastric cancer (GC). Because there are no standard treatments for PD, it is associated with a poor prognosis. Although clinicians have performed intraperitoneal chemotherapy for GC with PD, the outcome remains unsatisfactory. Therefore, the development of novel treatments and diagnostic tools for PD is expected to improve the prognosis of GC patients with PD. Notably, it is essential to elucidate the molecular mechanisms involved in the development of PD in GC. In this review, the molecular mechanisms of PD (three steps: detachment from the primary tumor, adaptation to the microenvironment of the peritoneal cavity, and attachment to peritoneal mesothelial cells) and new topics in GC are highlighted.

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Hypoxia and the extracellular matrix: drivers of tumour metastasis

Cited by 1,180 publications

References 192 publications

Intratumoral oxygen gradients mediate sarcoma cell invasion

Intratumoral oxygen gradients mediate sarcoma cell invasion

CCN family of proteins: critical modulators of the tumor cell microenvironment

Molecular mechanism of peritoneal dissemination in gastric cancer

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