Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers

Sugino, Takashi; Yamaguchi, Tomiko; Ogura, Go; Saito, Asami; Hashimoto, Takeaki; Hoshi, Nobuo; Yoshida, Sayaka; Goodison, Steve; Suzuki, Toshimitsu

doi:10.1186/1741-7015-2-9

Cited by 59 publications

(52 citation statements)

References 17 publications

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“…Recently, morphological studies from our group and other groups have revealed the development of sinusoid-like vessels that closely surround individual tumor clusters in HCC. [22][23][24] We also find that the existence of a vessel-surrounded tumor cluster is significantly associated with the incidence of intravascular endothelium-coated emboli and predicts an early relapse of HCC. 22 These findings suggest that certain types of vascular pattern may have a profound impact on HCC metastasis.…”

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confidence: 60%

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner

et al. 2015

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Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three-dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC 1 ) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell-derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC -xenografts but did not affect that of VETC 1 ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC 1 and VETC -HCC cells. In contrast to human VETC -cases, EMT signatures were rarely observed in VETC 1 cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. Conclusion: Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs. (HEPATOLOGY 2015;62:452-465) See Editorial on Page 343 T he current hypothesis of blood-borne metastasis holds that tumor cells must detach from the primary tumor, invade the extracellular matrix and vascular walls, survive in the circulation, extravasate from the vasculature, and grow at a new site.1,2 Accordingly, epithelial-mesenchymal transition (EMT) has been considered a key event for the epithelial tumor cells to lose cell-cell adhesion, acquire enhanced capacity for migration and invasion, and thereby dissociate from the

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confidence: 60%

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner

et al. 2015

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“…Tumor tissue fragments may have high clinical relevance as these are frequently found in lymph and blood vessels of cancer patients with poor prognosis Weidner, 2002). Interestingly, renal clear cell carcinomas, which frequently show constitutive VEGF-A expression, also frequently display a nodular phenotype and intravascular growth (Sugino et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…First, clinical and animal data show that for metastatic tumors in brains, lungs or livers, induction of angiogenesis is not a prerequisite as for these tumors the preexistent vascular bed may allow tumor growth (Pezzella et al, 1997;Al-Mehdi et al, 2000;Neves et al, 2001;Vermeulen et al, 2001;Kim et al, 2002;Kusters et al, 2002;Passalidou et al, 2002;Auguste et al, 2005). Secondly, recent reports demonstrated the presence of intravascular endothelium-covered tumor cell clusters in the primary tumor as origin of metastasis (Sugino et al, 1993(Sugino et al, , 2002(Sugino et al, , 2004. Clinical and preclinical data suggest that not the amount of circulating single tumor cells but rather that of circulating tumor cell clusters correlate with development of metastases (Fidler, 1973;Liotta et al, 1976;Glaves, 1983;Vlems et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

et al. 2007

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How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasionindependent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.

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“…The VEGFR-3-expressing endothelial cells that envelope the LAM cell clusters may serve to shield mutation-bearing LAM cells from immune surveillance against novel or ectopic surface antigens they express, such as the glycolipid GD-3 (126). Long dwell times of these "tumor emboli" in the pulmonary capillaries may facilitate metastasis by a process similar to that proposed for the angiogenesis-driven, "invasion-independent" mechanism described for endothelial cell-lined renal cell carcinoma clusters that gain access to the interstitium via surrounding venules (127,128).…”

Section: Figurementioning

confidence: 99%

Lymphangioleiomyomatosis — a wolf in sheep’s clothing

Henske

McCormack²

2012

J. Clin. Invest.

271

260

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Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease of women. LAM is caused by mutations in the tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network. Over the past 11 years, there has been remarkable progress in the understanding of LAM and rapid translation of this knowledge to an effective therapy. LAM pathogenic mechanisms mirror those of many forms of human cancer, including mutation, metabolic reprogramming, inappropriate growth and survival, metastasis via blood and lymphatic circulation, infiltration/ invasion, sex steroid sensitivity, and local and remote tissue destruction. However, the smooth muscle cell that metastasizes, infiltrates, and destroys the lung in LAM arises from an unknown source and has an innocent histological appearance, with little evidence of proliferation. Thus, LAM is as an elegant, monogenic model of neoplasia, defying categorization as either benign or malignant.

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Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers

Cited by 59 publications

References 17 publications

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner

Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

Lymphangioleiomyomatosis — a wolf in sheep’s clothing

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