The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

Eynden, Gert G. Van den; Majeed, Ali W.; Illemann, Martin; Vermeulen, Peter B.; Bird, Nigel C.; Høyer‐Hansen, Gunilla; Eefsen, Rikke Løvendahl; Reynolds, Andrew R.; Brodt, Pnina

doi:10.1158/0008-5472.can-12-3931

Cited by 183 publications

(183 citation statements)

References 108 publications

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“…Liver is a common site for metastases of a variety of cancers, including melanoma, breast, pancreatic, and colon cancers (1,2). For example, uveal melanoma, the most common primary intraocular tumor, has a 40% risk of metastasizing to the liver within 10 y of diagnosis of the primary tumor.…”

mentioning

confidence: 99%

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Xue

Yang²,

Qiao

et al. 2015

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

119

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With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd 3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd 3+ and a 10 11 -fold greater selectivity for Gd 3+ over Zn 2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r 1 /r 2 : 66.8 mmol −1 ·s −1 / 89.2 mmol −1 ·s −1 per particle). Using T 1 -and T 2 -weighted, as well as T 2 /T 1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.MRI | uveal melanoma | metastasis | contrast agents | T 2 /T 1 ratio imaging T umor metastasis is the main cause of nearly all human cancerrelated deaths. Liver is a common site for metastases of a variety of cancers, including melanoma, breast, pancreatic, and colon cancers (1, 2). For example, uveal melanoma, the most common primary intraocular tumor, has a 40% risk of metastasizing to the liver within 10 y of diagnosis of the primary tumor. Hepatic metastases, which occur in 95% of patients with uveal melanoma metastasis, result in death in almost all cases. This high death rate is related to the recognition of liver metastasis at a late clinical stage (at stage II or later in the TNM system) in which the metastatic uveal melanoma is resistant to currently available systemic chemotherapies (3, 4). The liver may also give rise to primary tumors such as hepatocellular carcinoma (HCC), which is the most common primary malignancy worldwide (5). However, currently there is no reliable way to detect primary liver cancer and hepatic metastases at early stages with high sensitivity and specificity.MRI is a widely used clinical imaging modality that provides exquisite soft-tissue contrast without using ionizing radiation (6, 7). More than 35% of MRI scans use MRI contrast agents, particularly paramagnetic gadolinium (Gd 3+ )-based contrast agents, which shorten T 1 and lead to an increase in MRI intensity (8). All clinically approved Gd 3+ -containing contrast agents are based on small chelators with relaxivity (r 1 and r 2 ) values around 4-6 mM −1 ·s −1 . Their low relaxivities severely limit the sensitivity of current MR imaging methods with respect to detection of lesions and treatment planning and monitoring. Repeat MRI scans are frequently requested for patients with ambiguous small lesions and are used as a routine follow-up modality for highrisk patients, but t...

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mentioning

confidence: 99%

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Xue

Yang²,

Qiao

et al. 2015

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

119

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“…Innate immune cells, such as Kupffer cells and natural killer (NK) cells, are known to play critical roles in the regulation of liver metastasis (3). Numerous highly specialized cell types are distributed within the sinusoidal structure of the liver, with hepatocytes composing a major proportion of the total number (4).…”

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confidence: 99%

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

Kimura

Inoue

Hangai

et al. 2016

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

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Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2-dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.liver metastasis | C-type lectin receptor | Dectin-2 | Kupffer cell | phagocytosis

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“…"The liver sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth" [30]. "Breast CSCs demonstrate an increased metastatic propensity in vitro, in vivo, and in clinical observation" [30].…”

Section: Discussionmentioning

confidence: 99%

“…"Breast CSCs demonstrate an increased metastatic propensity in vitro, in vivo, and in clinical observation" [30]. The question is why certain cancer display af inity towards one speci ic organ and not the others?…”

Section: Discussionmentioning

confidence: 99%

“…Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 patterns, re lecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment" [30].…”

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confidence: 99%

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Similarity between Some Biological Systems, Organotropism and Metastatic Process: Active Role Played By Secondary Organ?

Luisetto¹

2018

Insights Biol Med

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According to literature, about 90% of death from cancer is related to metastasis. Metastatic process present many similarity to some other biological processes. Once we have examined some relevant biomedical literature, by understanding the real causes of metastasis, it would become much more possible to introduce new therapeutic strategies to delay or in some cases even to stop this kind of killer process. Breast cancer, as an example, produces metastasis to different organs, which seems to be related to the subtype. We believe that a deep understanding of the roles of breast cancer cells and their interactions with the liver microenvironment in early breast cancer metastasis could be a crucial factor for the design and development of effective BCLM breast cancer liver metastases therapeutic strategies and to better understand the general process. Let's suppose the secondary organ or organs can be considered as incubator/s for the primary metastatic cells. What kind of consequences we can have in therapy fi eld if there is an active regulating role in determining the location of secondary cancers?Let's observe the role played by liver, bone marrow, CNS central nervous system, lungs, lymphocytes and other secondary locations/organs a little bit closer or maybe from a different angle let's suppose we try to come up with just a hypothesis. Just let's take this as a possibility, and we take the thread to see where it takes us.

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The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

Cited by 183 publications

References 108 publications

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

Similarity between Some Biological Systems, Organotropism and Metastatic Process: Active Role Played By Secondary Organ?

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