Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

Stessels, Filip; Eynden, Gert Van den; Auwera, Ilse Van der; Salgado, Roberto; Heuvel, Eva Van den; Harris, Adrian L.; Jackson, David G.; Colpaert, Cécile; Marck, Eric A. Van; Dirix, L.; Vermeulen, Peter B.

doi:10.1038/sj.bjc.6601727

Cited by 187 publications

(180 citation statements)

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“…For example, human breast tumours that have metastasized to liver show this phenotype. They have been reported to exhibit little evidence for hypoxia (indicated by expression of the endogenous hypoxia marker protein carbonic anhydrase IX) and express low levels of VEGF 125,126 . Hepatic metastases of colorectal cancer, by contrast, show high levels of carbonic anhydrase IX and increased VEGF and clearly exhibit angiogenesis 125 .…”

Section: Hypoxia and Angiogenesismentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Hypoxia and Angiogenesismentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Reports have suggested differences between primary tumours and secondary sites and between different secondary sites. Whereas primary breast tumours grow angiogenesis dependently, we demonstrated that 90% of breast cancer liver metastases grow according to an angiogenesis-independent replacement pattern (Stessels et al, 2004). The growth of breast cancer LN metastases, on the contrary, was angiogenesis dependent and angiogenesis and hypoxia in the metastases were correlated with angiogenesis and hypoxia in the primary tumours .…”

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confidence: 72%

Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer

et al. 2006

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We studied the presence of lymphangiogenesis in lymph node (LN) metastases of breast cancer. Lymph vessels were present in 52 of 61 (85.2%) metastatically involved LNs vs 26 of 104 (25.0%) uninvolved LNs (Po0.001). Furthermore, median intra-and perinodal lymphatic endothelial cell proliferation fractions were higher in metastatically involved LNs (Po0.001). This is the first report demonstrating lymphangiogenesis in LN metastases of cancer in general and breast cancer in particular. Lymph node (LN) status is the most important prognostic factor for patients with breast cancer. The presence and the extent of axillary LN metastases reflect the probability that the cancerous process has spread through the body and both are strongly correlated with the development of distant metastases and with shortened disease-free and overall survival. Lymph node metastases are more than passive tumour deposits. Metastatic tumour sites are capable of inducing a vascular stroma and can actively contribute to tumour progression and to further metastatic spread. To what extent processes involved in progression of primary tumours, such as angiogenesis and lymphangiogenesis, contribute to progression of secondary sites is largely unknown. Reports have suggested differences between primary tumours and secondary sites and between different secondary sites. Whereas primary breast tumours grow angiogenesis dependently, we demonstrated that 90% of breast cancer liver metastases grow according to an angiogenesis-independent replacement pattern (Stessels et al, 2004). The growth of breast cancer LN metastases, on the contrary, was angiogenesis dependent and angiogenesis and hypoxia in the metastases were correlated with angiogenesis and hypoxia in the primary tumours . Guidi et al (2000) demonstrated that the presence of vascular hot spots in LN metastases, but not in the primary breast tumours was associated with decreased survival.In the present study, we compared the expression of the lymphatic endothelium-specific markers Prox-1, LYVE-1 and podoplanin in metastatically involved and uninvolved LNs of patients with breast cancer. Prox-1 and LYVE-1 are, respectively, a transcription factor and a hyaluronan receptor that show specificity for lymphatic endothelial cells. D2-40 was originally described as a selective monoclonal antibody to a M r 40 000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope in lymphatic endothelium (Kahn and Marks, 2002). Recently, the D2-40 antibody has been shown to specifically recognise podoplanin, a glomerular podocyte membrane protein (Schacht et al, 2005) and has been shown to be a very sensitive and specific marker for lymphatic endothelium in most tissues (Evangelou et al, 2005) and especially in breast cancer . We investigated the presence and extent of lymphangiogenesis in LN metastases of breast cancer using the podoplanin antibody. MATERIALS AND METHODS Patients and samplesOne hundred and ten patients with operable breast cancer were included in this study, 49 patients with LN-neg...

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“…Furthermore, the growth pattern of the skin deposit correlated with the growth pattern of the primary tumour. Breast cancer liver metastases, on the other hand, almost always show a 'replacement' growth pattern (Stessels et al, 2004): breast cancer cells replace hepatocytes at the tumour/liver interface with conservation of the liver plate architecture and cooption of the sinusoidal vasculature of the liver. Almost no hypoxia and no angiogenic switch is seen.…”

Section: Discussionmentioning

confidence: 99%

“…Although primary tumour growth in breast cancer is angiogenesis dependent, we previously showed that 96% of liver metastases of breast cancer grow according to a nonangiogenic replacement pattern, marked by replacement of the hepatocytes by tumour cells without any desmoplastic reaction (Stessels et al, 2004). Thus, breast cancer liver metastases grow by coopting the sinusoidal vessels.…”

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confidence: 98%

Angiogenesis and hypoxia in lymph node metastases is predicted by the angiogenesis and hypoxia in the primary tumour in patients with breast cancer

et al. 2005

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Hypoxia and angiogenesis are important factors in breast cancer progression. Little is known of hypoxia and angiogenesis in lymph node metastases of breast cancer. The aim of this study was to quantify hypoxia, by hypoxia-induced marker expression levels, and angiogenesis, by endothelial cell proliferation, comparing primary breast tumours and axillary lymph node metastases. Tissue sections of the primary tumour and a lymph node metastasis of 60 patients with breast cancer were immunohistochemically stained for the hypoxia-markers carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1a (Hif-1a) and DEC-1 and for CD34/Ki-67. Endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. On haematoxylin -eosin stain, the growth pattern and the presence of a fibrotic focus were assessed. Hypoxia-marker expression, ECP% and TCP% in primary tumours and in lymph node metastases were correlated to each other and to clinico-pathological variables. Median ECP% and TCP% in primary tumours and lymph node metastases were comparable (primary tumours: ECP% ¼ 4.02, TCP% ¼ 19.54; lymph node metastases: ECP% ¼ 5.47, TCP% ¼ 21.26). ECP% correlated with TCP% (primary tumours: r ¼ 0.63, Po0.001; lymph node metastases: r ¼ 0.76, Po0.001). CA9 and Hif-1a expression were correlated (primary tumours P ¼ 0.005; lymph node metastases Po0.001). In primary tumours, CA9 and Hif-1a expression were correlated with DEC-1 expression (P ¼ 0.05), presence of a fibrotic focus (Po0.007) and mixed/expansive growth pattern (Po0.001). Primary tumours and lymph node metastases with CA9 or Hif-1a expression had a higher ECP% and TCP% (Po0.003); in primary tumours, mixed/expansive growth pattern and fibrotic focus were characterised by higher ECP% (P ¼ 0.03). Furthermore, between primary tumours and lymph node metastases a correlation was found for ECP%, TCP%, CA9 and Hif-1a expression (ECP% r ¼ 0.51, Po0.001; TCP r ¼ 0.77, Po0.001; CA9 and Hif-1a Po0.001). Our data demonstrate that the growth of breast cancer lymph node metastases is angiogenesis dependent and that angiogenesis and hypoxia in the primary tumour predict angiogenesis and hypoxia in the lymph node metastases. Together with previous findings in breast cancer liver metastases, which grow in 96% of cases angiogenesis independently, these data suggest that both the intrinsic growth characteristics and angiogenic potential of breast cancer cells and the site-specific tumour microenvironment determine angiogenesis and hypoxia in breast cancer. British Journal of Cancer (2005) Breast cancer is the most frequent neoplasm in women and the most frequent cause of death in women between 35 and 55 years of age (Uzzan et al, 2004). Although loco-regional spread and recurrence of the disease can be debilitating, metastasis to distant organs is the leading cause of breast cancer-related death. Traditional metastasis models of breast cancer include the regional lymph node basin as the first station in the metastatic cascade from where further haematogenous diss...

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Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

Cited by 187 publications

References 28 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer

Angiogenesis and hypoxia in lymph node metastases is predicted by the angiogenesis and hypoxia in the primary tumour in patients with breast cancer

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