Cancer metastases: challenges and opportunities

Abstract

Cancer metastasis is the major cause of cancer morbidity and mortality, and accounts for about 90% of cancer deaths. Although cancer survival rate has been significantly improved over the years, the improvement is primarily due to early diagnosis and cancer growth inhibition. Limited progress has been made in the treatment of cancer metastasis due to various factors. Current treatments for cancer metastasis are mainly chemotherapy and radiotherapy, though the new generation anti-cancer drugs (predominantly neutralizing antibodies for growth factors and small molecule kinase inhibitors) do have the effects on cancer metastasis in addition to their effects on cancer growth. Cancer metastasis begins with detachment of metastatic cells from the primary tumor, travel of the cells to different sites through blood/lymphatic vessels, settlement and growth of the cells at a distal site. During the process, metastatic cells go through detachment, migration, invasion and adhesion. These four essential, metastatic steps are inter-related and affected by multi-biochemical events and parameters. Additionally, it is known that tumor microenvironment (such as extracellular matrix structure, growth factors, chemokines, matrix metalloproteinases) plays a significant role in cancer metastasis. The biochemical events and parameters involved in the metastatic process and tumor microenvironment have been targeted or can be potential targets for metastasis prevention and inhibition. This review provides an overview of these metastasis essential steps, related biochemical factors, and targets for intervention.

Keywords: Adhesion; BM, basement membrane; CAFs, cancer-associated fibroblasts; CAMs, cell adhesion molecules; CAT, collective amoeboid transition; CCL2, chemokine (C–C motif) ligand 2; CCR3, chemokine receptor 3; COX2, cyclooxygenase 2; CSF-1, chemokine colonystimulating factor–1; CTGF, connective tissue growth factor; CXCR2, chemokine receptor type 2; Cancer; Col, collagen; DISC, death-inducing signaling complex; Detachment; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, EGF receptor; EMT, epithelial–mesenchymal transition; FAK, focal adhesion kinase; FAs, focal adhesions; FGF, fibroblast growth factor; FN, fibronectin; HA, hyaluronan; HGF, hepatocyte growth factor; HIFs, hypoxia-inducible factors; IKK, IκB kinase; Invasion; JAK, the Janus kinases; LN, laminin; MAPK, mitogen-activated protein kinase; MAT, mesenchymal to amoeboid transition; MET, mesenchymal–epithelial transition; MMPs, matrix metalloproteinases; Metastasis; Migration; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; STATs, signal transducers and activators of transcription; TAMs, tumor-associated macrophages; TGF-β, transforming growth factor β; TME, tumor microenvironment; VCAMs, vascular cell adhesion molecules; VEGF, vascular endothelial growth factor; VN, vitronectin.

Graphical abstract

Figure 1

Metastatic cascade. Metastatic cells detach from the primary tumor site, migrate and invade through the BM and ECM, enter the blood or lymphatic vessels (intravasation), travel in the blood/or lymphatic vessels, leave the blood or lymphatic vessels (extravasation), adhere and grow at a distal site.

Figure 2

Illustration of cell detachment, cell–cell adhesion and cell–matrix adhesion of epithelial cells by E-cadherins and integrins respectively. Cell detachment: cell detachment from ECM can occur through breakage of adhesion proteins at both intracellular site and extracellular site. Cytosolic cleavage can be achieved through both mechanic forces and enzymatic cleavage while extracellular cleavage is primarily achieved through cleavage by proteases such as MMP. Cell–matrix adhesion by integrins: cell–matrix adhesion is achieved through interaction of integrins with intracellular cytoskeleton and extracellular ECM components. The large extracellular domain of integrin binds to ECM components such as FN, LN, Col, fibrinogen, and VN. The intracellular domain is connected to cytoskeleton through focal adhesions. Cell–cell adhesion by cadherins: cell A and cell B are tightly linked by E-cadherins at adherent junction. The extracellular domain of the same type of cadherin (homodimers) (e.g., E-cadherin with E-cadherin) from the adjacent cells were tightly linked in a calcium-dependent manner. The intracellular domain of the cadherin is connected to cytoskeleton (α-actinin, vinculin, and actin cytoskeleton) through linker proteins (α-catenin, β-catenin and p120 catenin). Cell adhesion among other cells is achieved in a similar way except different CAMs are employed.

Figure 3

Invasive migration of metastatic cancer cells. A metastatic cell reorganizes its actin cytoskeleton and concomitantly forms F-actin-rich membrane protrusions (lamellipodia, filopodia, podosomes, and invadopodia) at the leading edge. The protrusions are critical for migration and invasion through the use of mechanic forces and protease activities. They serve as cells׳ sensory organ (filopodia) for signals like chemoattractants, or the main organelle for cell locomotion (lamellipodia), or for both cell locomotion and degradation of the ECM through the use of proteases (invadopodia).

Figure 4

Agents that reverse anoikis-resistance.

Figure 5

Structures of CAM inhibitors.

Figure 6

Chemical structures of small molecules that inhibit growth factor signaling pathways.

Figure 7

Structures of representative MMP inhibitors.

Figure 8

Structures of representative uPA inhibitors.

Figure 9

Chemical structures of representative compounds that interfere with the inflammation process. CCL2: chemokine (C–C motif) ligand 2; CSF-1: chemokine colonystimulating factor-1; JAK: Janus kinases; IKK: The IκB kinase (IKK) complex; TGF-β: transforming Growth Factor β; CXCR2: chemokine receptor type 2; CCR3: chemokine receptor; COX2: cyclooxygenase 2.

Figure 10

Chemical structures of representative compounds that interfere with HIF-1 function.

Figure 11

Chemical structure of LY2157299.