Surviving at a distance: organ specific metastasis (2024)

The publisher's final edited version of this article is available at Trends Cancer

Box 1

The metastatic cascade

Overt metastasis is the final manifestation of a series of stochastic events that are collectively called the “metastatic cascade”. The cascade can be parsed into distinct steps: (1) local invasion and intravasation, (2) dissemination in the circulation, (3) arrest at the distant site, (4) extravasation, (5) survival as micrometastasis, and (6) colonization of target organs. These steps have been extensively reviewed in [1, 2, 122].

• Step 1. To invade from the confined primary tumor to the adjacent parenchyma, tumor cells utilize the action of a variety of extracellular proteases, including matrix metalloproteinases (MMPs) and cathepsins, which break down extracellular matrix (ECM) and trigger the release growth factors that influence tumor growth and invasion [79, 123]. The invasive front of a tumor is an important interface at which cancer and stromal cells interact closely [124]. Myeloid cells accumulate at the invasive front, generating an immunosuppressive environment. Tumor-associated macrophages and fibroblasts promote the invasion of cancer cells by producing pro-migratory factors or depositing fibrillar collagen [125–128]. Departure from a primary tumor is favored by the epithelial-to-mesenchymal transition (EMT) of cancer cells. EMT involves a loss of intercellular adhesion, epithelial polarization and the gain of mesenchymal traits [122]. In cancer cells, EMT supports self-renewal, motility and invasiveness, traits that favor metastatic dissemination [122, 129, 130]. A leaky neovasculature generated by the primary tumor contributes to easier access to the circulation.

• Step 2. Cancer cells may invade and intravasate as single cells or as multi-cellular clusters and associate with non-neoplastic cells, which may enhance their survival during dissemination [120, 125, 131]. At distant organ sites, circulating tumor cells arrest in narrow capillary beds and extravasate. Rapid physical trapping due to vasculature size likely plays a major role in this process [132]. The capacity to arrest at distant organs may also be determined by specific functions of the cancer cells, e.g. by forming adhesive connections in specific organs as it has been described for breast cancer in the lung vasculature [133].

• Step 3, 4. Cancer cells lodged in the microvasculature may initiate intraluminal growth and form an embolus that eventually ruptures the blood vessel or, more frequently, cancer cells may extravasate directly into the tissue parenchyma by penetrating the microvascular wall. In the bone marrow or the liver, the vasculature is fenestrated and poses a lower physical barrier than in other organs such as the lungs or the brain [1, 2]. There, the vasculature is surrounded by a tight basem*nt membrane and additionally reinforced by pericytes and astrocytes, which requires specialized functions by the cancer cells to extravasate into the parenchyma [14, 64].

• Step 5, 6. The vast majority of cancer cells that extravasate into the parenchyma will die, but a minority of these cells may enter a period of dormancy and survive for months to decades. From such disseminated tumor cell populations a few cancer cells may re-initiate growth and establish a full-fledged tumor at the distant site.

Bone metastasis

60–85% of patients with metastatic breast and prostate cancer harbor bone metastases, often resulting in pathological fractures, chronic pain, and neurological compression syndromes [41]. The small blood vessels in the bone marrow, called sinusoids, are lined with fenestrated endothelia to allow the traffic of hematopoietic cells. The bone marrow sinusoids are likely more permissive to circulating tumor cells (CTCs) than are other types of capillaries. In addition, bone matrix cells like osteoblasts secrete a variety of chemo-attracting factors (e.g. CXCL12, RANKL, OPN, or BMPs) that recruit cancer cells to the bone marrow [41, 42] (Figure 2, top).

After extravasation into the bone marrow, cancer cells may benefit from abundantly expressed soluble factors, such as CXCL12 and IGF1, that stimulate PI3K-AKT signaling – a pathway well known to enhance cancer cell survival in challenging environments [43] (Figure 2, top). Cancer cells with elevated Src signaling and high expression levels of CXCR4 (the receptor for CXCL12) are especially primed to utilize the physiological survival signals in the bone marrow, increasing the probability of establishing overt metastasis later on [21, 26]. In addition, high Src activity has been shown to counteract pro-apoptotic signaling of TRAIL, a cytokine also present in bone metastatic lesions [21, 44]. These findings from animal models are also reflected in clinical datasets in which CXCR4 expression and expression of the Src signature in tumor cells is associated with breast cancer bone relapse [21].

The need to find supportive niches within an organ is of importance for the survival of disseminated metastatic stem cells [45]. Cancer cells may take up residence in stem cell niches of the bone marrow. Prostate cancer cells compete with hematopoietic stem cells (HSCs) for occupancy of stem cell niches [46] and breast cancer cells can occupy osteogenic niches [47] (Figure 2, top). In these niches, cancer cells may benefit from heterotypic adherens junctions between E-cadherin on cancer cells and N-cadherin on osteogenic cells. E-cadherin expression correlates with bone metastasis in patient samples and early disruption of the adherens junctions reduces bone metastasis in mouse models [47]. Similarly, the expression of α4β1 integrin and its ligand, vascular cell adhesion molecule-1 (VCAM1), facilitates microenvironmental crosstalk in the bone marrow to promote the expansion of micrometastases in pre-clinical models [28, 48, 49].

During the final phase of overt colonization metastatic cancer cells can also actively modify the bone microenvironment in their favor, by disturbing the complex and tightly regulated network of signals that control bone homeostasis by regulating osteoblasts and osteoclasts (Figure 2, bottom). Depending on the signals released from cancer cells, bone metastases manifest as osteoblastic lesions, osteolytic lesions, or a combinations thereof [41, 50]. In osteoblastic lesions, which are typically of prostate cancer metastasis, tumor cells stimulate bone matrix deposition by osteoblasts, resulting in increased bone density and eventual displacement of the bone marrow [51]. Factors secreted by prostate cancer cells that promote osteoblastic bone metastasis include fibroblast (FGFs) insulin-like (IGFs), vascular endothelial (VEGF), and platelet derived growth factor (PDGF) as well as endothelin 1 (ET1), WNT family members, and bone morphogenetic proteins (BMPs) [41, 51–55].

In osteolytic lesions, which are caused most commonly by breast cancer and lung cancer, the metastatic cells activate bone resorbing osteoclasts, which produce collagenases and other proteases, that degrade ECM proteins and demineralize the bone matrix [41, 56]. Taking center stage in the formation of osteolytic bone metastasis is nuclear factor-kB ligand (RANKL) signaling [41]. Tumor cell-derived PTHrP, IL-11, IL-6, and TNF-α cue osteoblasts to release RANKL, which induces osteoclast formation and the subsequent resorption of the bone [41, 50]. Bone metastatic cancer cells also secrete MMPs, which increase local RANKL activity, either directly by cleaving and releasing membrane-bound RANKL [57], or indirectly, by reducing the level of the RANKL antagonist osteoprotegrin [58].

One consequence of bone resorption in osteolytic metastasis is the release of growth factors that are normally embedded in the mineralized bone matrix (Figure 2, bottom). The released growth factors then stimulate tumor growth, leading to the production of additional osteolytic and osteoblastic factors, and resulting in the ‘vicious cycle’ of bone metastasis [41, 50, 56]. TGF-β is abundant in the bone matrix and is released during osteoclastic bone resorption [41]. In breast and melanoma models, TGF-β signaling plays an essential role in the establishment of bone metastasis. TGF-β signaling is activated in bone metastasis of breast cancer patients and inhibition of the TGF-β pathway reduces bone metastasis formation in pre-clinical models [24, 59–61]. Recently, it has been shown that bone tropic prostate cancer cells also benefit from TGF-β signaling, which is further amplified by reduced levels of PMEPA1, a negative regulator of TGF-β signaling. In patients, PMEPA1 levels decreased in metastatic lesions compared with the primary tumor and low PMEPA1 levels correlated with worse prognosis [62].

Additional mechanisms that promote osteolytic bone metastasis involve the Notch ligand Jagged1 (JAG1), the expression of which is also regulated by TGF-β. JAG1 overexpression mediates bone metastasis in a human hormone receptor-negative (‘triple negative’) breast cancer cell line [24] and is associated with bone metastatic relapse in different patient cohorts [30]. In xenograft models, JAG1 promotes osteolytic bone metastasis by activating Notch signaling in osteoblasts, which induces the secretion of IL6 and directly activates osteoclast differentiation [30] (Figure 2, bottom). Osteoclast differentiation is also influenced by tumor-derived factors (e.g. soluble intracellular adhesion molecule-1, sICAM-1), which induce widespread changes in microRNA abundance [31]. In in vitro experiments osteoclast differentiation could be blocked by the ectopic expression of several microRNAs, which target osteoclast genes. In a xenograft model, the delivery of these micro RNAs inhibited osteoclast activity and reduced osteolytic bone metastasis from breast cancer cells. Clinically, serum levels of sICAM-1 and two microRNAs that were elevated during osteoclast differentiation, mir-16 and mir-378, are associated with bone metastasis burden [31]. These examples show that factors secreted by cancer cells can modulate the bone metastatic microenvironment and determine the type of bone metastases formed.

Lung metastasis

Lung metastasis is frequent in different types of cancer, including breast cancer, gastrointestinal tumors, renal carcinomas, melanoma, different types of sarcomas, and lung cancer itself [5]. Lung capillaries are lined with endothelial cells that are surrounded by a basem*nt membrane and adjacent alveolar cells [1]. To cross these structural obstacles, breast cancer and melanoma cells express specific mediators such as SPARC and the TGF-β inducible factor angiopoietin-like 4 (ANGPTL4) and the secreted C-terminal fibrinogen-like domain of angiopoietin-like 4 (cANGPTL4) [63–65]. The expression of these mediators enhances the extravasation of tumor cells in the lung by dissociating the cell-cell junctions between endothelial cells (Figure 3). Other factors expressed by cancer cells are the EGF receptor ligand epiregulin, the prostaglandin synthase COX2, and the metalloproteinases MMP1 and MMP2, which foster the breaching of lung capillaries to seed metastasis [66]. All these mediators are up-regulated in breast tumors and their expression predicts relapse to the lungs [16, 63, 66], reinforcing the concept that metastatic traits required in early steps of the metastatic cascade are already selected for in the primary tumor, where they may play a different role in processes such as tumor angiogenesis.

After extravasation in the lung parenchyma, tumor-stroma interactions play a critical role in amplifying the output of survival and stemness pathways in cancer cells, consequently increasing their chances of surviving (Figure 3). In an MMTV-driven polyoma middle T (PyMT) mouse breast cancer model, lung metastatic cancer stem cells stimulate the expression of the extracellular matrix (ECM) protein periostin in lung fibroblasts via secretion of TGF-β3 [67]. Increased periostin levels recruit WNT ligands and stimulate WNT signaling preferentially in cancer stem cells, ultimately promoting lung colonization [67]. In the ECM, periostin tightly interacts with the hexameric glycoprotein tenascin C (TNC) [68]. TNC is expressed at the invasive front of tumors where it also binds to fibronectin, integrins and syndecan membrane proteoglycan, and is associated with poor prognosis and lung relapse in breast cancer patients [69]. TNC expression by fibroblasts or the tumor cells amplifies the Notch signaling output, and promotes survival of the tumor cells and their colonization of the lung [69, 70]. As the metastatic lesion grows and recruits cancer-associated fibroblasts, tumor cell derived TNC is joined by TNC from the stroma in this supportive role [69]. Lung tropic human breast cancer cells express high levels of VCAM-1, which is engaged by α4β1-integrins on tumor-associated macrophages. In xenograft models this interaction triggers VCAM-1 activation of ezrin, which subsequently enhances PI3K–Akt signaling in the cancer cells and increases their survival [71].

In addition to these interactions with the metastatic niche, cell intrinsic mechanisms are also essential for outgrowth of disseminated tumor cells. For example, the expression of inhibitor of differentiation 1 (ID1) and ID3 in breast cancer cells supports metastasis initiation after infiltration of the target parenchyma [72]. ID1 is under the control of TGF-β signaling and induces mesenchymal-epithelial transition (MET) by antagonizing the transcription factor Twist 1 at the metastatic site. Loss of ID1 dramatically reduced lung colonization in a xenograft model [73]. The microRNA mir-200 is intricately linked to the EMT-MET program and its overexpression promotes metastatic colonization of the lung. In addition to regulating E-cadherin, expression of mir-200 promotes metastatic colonization by targeting Sec23a, which regulates the secretion of metastasis suppressive proteins IGFBP4 and Tinagl1 [74]. Metastatic cells in the lungs may also have to overcome antagonistic signals from the stroma [75]. For example, BMP signals can promote differentiation of allograft breast cancer cells in the lungs. In this model, the BMP-sequestering protein Coco promotes metastatic outgrowth [76] (Figure 3).

Brain metastasis

Metastasis to the CNS principally involves the brain parenchyma and the leptomeninges, and it has a particularly poor prognosis with high morbidity and mortality. The median survival of patients with brain metastasis is in the order of months and few effective treatments are currently available [77]. More than half of brain metastasis derives from lung adenocarcinoma, followed by breast cancer and melanoma [5]. To enter the brain parenchyma, cancer cells must traverse micro-capillary walls that constitute the blood-brain barrier, which consists of tightly adjoined endothelial cells that are lined by a basem*nt membrane, pericytes, and astrocyte foot processes [78]. To cross this barrier and access the brain parenchyma, cancer cells require specialized mechanisms. Some of the molecular mediators of this process have been identified, including the sialyltransferase ST6GalNac5, COX2, HB-EGF, MMP-2, mir-105, and the protease cathepsin S [14, 79, 80] (Figure 4).

Metastatic colonization of the brain proceeds with a close apposition of cancer cells at the abluminal side of the microcapillaries [81, 82]. Small lesions often develop without establishing new vasculature [83]. Recently, lung cancer and breast cancer metastatic cells were shown to express the cell adhesion molecule L1CAM for spreading on the basem*nt membrane of brain capillaries after extravasation into the brain parenchyma (Figure 4). Brain metastatic cells also produce specific serpin protease inhibitors to prevent L1CAM cleavage by astrocyte-derived plasminogen activator (PA) [84]. High expression of SerpinB2 and Neuroserpin correlates with lower brain metastasis-free survival in patients with lung adenocarcinoma [84]. Integrins also play a critical role in mediating brain metastatic cell spreading and angiogenesis [85, 86]. Human lung adenocarcinoma and murine myeloma cells that reached mouse brain tissue and failed to establish required β1 integrin mediated adhesion to the vascular basem*nt membrane were less efficient at forming overt brain metastasis [87, 88].

Metastatic cancer cells encounter a variety of resident cell types in the brain parenchyma. Astrocytes can provide a growth-permissive microenvironment to infiltrated cancer cells, first, however, cancer cells must evade astrocyte induced cell death. In xenograft models of brain metastasis, activated astrocytes overexpress the pro-apoptotic cytokine Fas ligand (FasL) and release it from a membrane-anchored form by the action of PA to kill infiltrated metastatic cells. Brain metastatic cells express anti-PA serpins that shield cancer cells from PA-released FasL [84]. The surviving cancer cells can induce astrocytes to establish Notch signaling [25] and endothelin production, which favor metastasis in experimental systems [89, 90]. Conversely, cancer cells can increase the density of astrocytes by promoting the differentiation of neural progenitor cells towards the astrocyte lineage [91] (Figure 4).

The contribution of other brain cells, including oligodendrocytes, pericytes, microglia, or neurons, is less defined. Although brain metastatic cells need to neutralize cytotoxic microglia signals, microglia infiltration correlates with metastatic progression [81, 92]. Brain metastatic cells may up-regulate GABA transporters and utilize neuron-released GABA neurotransmitter as a metabolite, supporting outgrowth in the brain [93] (Figure 4).

The WNT pathway was identified to support colonization of brain and bone by KRAS-mutant and EGFR-mutant human lung adenocarcinoma cells [20]. Clinically, a specific WNT responsive gene signature is associated with metastatic relapse in lung adenocarcinoma patients [20]. Two WNT regulated genes, Lef1 and HoxB9, were specifically implicated in metastatic cell invasiveness and colony formation [20]. Brain metastases in patients show up-regulation of WNT target genes [94].

Liver metastasis

The liver is the most common site of distant metastasis in solid tumors. Gastrointestinal cancers such as CRC, pancreatic cancer and tumors of the gallbladder, which are drained by the enterohepatic circulation, reach the liver first. As such, the liver provides a large number of cancer cells with ample opportunity to arrest, extravasate, and colonize the hepatic parenchyma [22]. Indeed, a recent study found a higher number of circulating CRC cells in the portal venous blood than in the peripheral blood, suggesting that a significant percentage of tumor cells are trapped in the liver [95]. Other primary tumors that metastasize to the liver include lung and breast cancers [4, 5]. Uveal (ocular) melanoma almost exclusively relapses to the liver, providing a clear indication that, beyond circulation patterns, certain compatibilities of metastatic cells with the host stroma also count in organ-specific metastasis [96].

In contrast to the vessels in the brain or the lungs, the hepatic vasculature is fenestrated (sinusoidal endothelium) and lacks an organized sub-endothelial basem*nt membrane. Therefore, cancer cell extravasation is less restricted in the liver than it is in the brain or the lungs, as shown in quantitative cell-tracking studies in mice [12]. However, the liver parenchyma is rich in cells of the innate immune system, potentially posing a obstacle to cancer cells. Indeed, the neutralization of pro-apoptotic TRAIL on resident natural killer cells in the liver increases experimental metastasis [97] (Figure 5).

Certain liver parenchyma cell types favor metastatic outgrowth (Figure 5). In experimental models, claudin-2-mediated cell-cell interactions between breast cancer cells and hepatocytes led to induction of c-Met and stimulated metastasis to the liver [98]. In an allograft model, exosome vesicles released by murine pancreatic ductal adenocarcinoma cells caused TGF-β secretion, stimulated fibronectin production by hepatic stellate cells, and triggered a recruitment of bone-marrow derived macrophages [99]. The macrophage migration inhibitory factor (MIF) was highly enriched in murine and human pancreatic cancer exosomes, and its blockade inhibited metastasis in the mice [99] (Figure 5). CRC and lung cancer cells mobilize myeloid cell populations through soluble factors, such as CCL2 or IL6, that promote liver metastasis [100, 101] (Figure 5).

Certain cancer cells express the glycosyltransferases St6GalnAc4 and C2GnT2, which alter the glycosylation of a Galectin-3 ligand on tumor cells and thereby increase interaction with galectin-3 expressed on myeloid cells [101] (Figure 5). Clinically, aberrant glycosylation and high galectin-3 levels are associated with metastatic progression [101, 102]. Another significant case of metastatic interaction with the hepatic microenvironment is provided by CRC stem cells. The cells are often unresponsive to TGF-β owing to mutations that disable the TGF-β receptors or the SMAD signal transducers proteins. However, these cells abundantly secrete TGF-β, which enhances metastasis formation in the liver by activating a paracrine loop with production of IL-11 from stromal fibroblasts. IL-11 then activates STAT3 signaling in CRC stem cells to support their survival in the liver [27] (Figure 5).

Proliferating cancer cells in the liver have high biosynthetic demands and compete with hepatocytes for glycolytic substrates. In vivo screens identified two microRNAs (miR-551a and miR-483) that were down regulated in liver-tropic CRC cells leading to increased expression of the creatine kinase brain-type (CKB) [103]. The cancer cells benefit from high levels of creatine in the liver, which CKB coverts into phosphocreatine that the CRC import for their bioenergetic needs [103] (Figure 5).

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