Cancer cell invasion: treatment and monitoring opportunities in nanomedicine

Abstract

Cell invasion is an intrinsic cellular pathway whereby cells respond to extracellular stimuli to migrate through and modulate the structure of their extracellular matrix (ECM) in order to develop, repair, and protect the body's tissues. In cancer cells this process can become aberrantly regulated and lead to cancer metastasis. This cellular pathway contributes to the vast majority of cancer related fatalities, and therefore has been identified as a critical therapeutic target. Researchers have identified numerous potential molecular therapeutic targets of cancer cell invasion, yet delivery of therapies remains a major hurdle. Nanomedicine is a rapidly emerging technology which may offer a potential solution for tackling cancer metastasis by improving the specificity and potency of therapeutics delivered to invasive cancer cells. In this review we examine the biology of cancer cell invasion, its role in cancer progression and metastasis, molecular targets of cell invasion, and therapeutic inhibitors of cell invasion. We then discuss how the field of nanomedicine can be applied to monitor and treat cancer cell invasion. We aim to provide a perspective on how the advances in cancer biology and the field of nanomedicine can be combined to offer new solutions for treating cancer metastasis.

Figure 1

Cell invasion process. a) Invasive cells from a primary tumor intravasate into surrounding vasculature to enter the circulation, and extravasate into a secondary location to form a metastatic tumor. Invasive cells from the primary tumor can also invade the surrounding tissue to form a micro–tumor within the same organ. b) Expanded view of an invading cell, a process that involves: (I) protrusion of the leading edge of the cell into the surrounding ECM; (II) formation of focal contacts between the cell and ECM to provide traction; (III) proteolysis of ECM to provide room for infiltration; (IV) cell contraction to pull itself forward towards the invasive direction; and (V) detachment of the trailing edge of the cell from the ECM and surrounding cells to move forward. Additionally, throughout this process, (a) transcription factors promote the expression of pro-invasion molecules, (b) inward and outward flux of ions regulate cell volume and protein function, and (c) water efflux modulates cell volume.

Figure 2

General architecture and assembly of a multifunctional NP. Generally, a solid NP core is coated with a biocompatible polymer coating which can then be derivatized with targeting agents, fluorophores, radionuclides, gene therapeutics, and chemotherapy drugs.

Figure 3

Summary of data obtained through this original study that demonstrated the applicability of NPCP-CTX NP’s for delineating tumor boundaries through in vivo MRI, and in vivo fluorescence imaging. a) In vivo MR images of autochthonous medulloblastoma tumors in genetically engineered ND2:SmoA1 acquired before and 48 hrs after administration of either NPCP-CTX or NPCP NPs. b) In vivo NIRF imaging of ND2:SmoA1 mice injected with either NPCP-CTX or NPCP-Cy5.5, or receiving no injection (from left to right). Post-injection ex vivo fluorescence images of mice brains from the same mice following necropsy are shown in the inset of b. The spectrum gradient bar at right corresponds to fluorescence intensity (p/s/cm²/sr) of images. Reprinted by permission from the American Association Cancer Research , copyright 2009.

Figure 4

Dual-Labeled ACPPD. (A–D) Example of HT1080 xenograft treated with ACPPD dually labeled with gadolinium and Cy5. Preoperative MR image of mouse showing contrast uptake in tumor (A, black arrow). Following skin incision and retraction, the tumor (black arrow) on the left chest wall was visible with Cy5 fluorescence (B). Following initial surgery, repeat MRI (C) showed a small area of tissue with increased gadolinium uptake (D inset, white arrowhead). This area of tissue was identified using fluorescence imaging at a second surgery. Histological analysis of this tissue confirmed the presence of cancer cells (D). (Scale bar: 100 μm). (E–H) Example of MDA-MB 435 xenograft treated with ACPPD dually labeled with gadolinium and Cy5. Preoperative MR image of mouse showing contrast uptake in tumor (E, black arrow). Following skin incision and retraction, the tumor (black arrow) on the left chest wall was visible with Cy5 fluorescence (F). Tumor was resected using ACPPD-Cy5 imaging guidance until all visible fluorescence was completely removed (G). Repeat MR imaging following surgery showed complete removal of all tumor (H). Reproduced with permission from National Academy of Sciences, USA , copyright 2010.

Figure 5

Membrane dynamics in metastatic cancer cells in vessels. A, imaging of cells in the bloodstream. Cells are shown after 1 s, 17 s, and 41 s. Yellow lines show outlines of cancer cells. Red dotted lines show outlines of vessels determined by superimposed images of autofluorescent blood cells. White dotted lines indicate outlines of red blood cells. B, trajectory of the barycentric position of the cell in A at every 2 s (green line). C, fluorescent image of a cell adhering to the inner vascular surface without directional movement. The yellow line shows an outline of the cancer cell. D, trajectory of the barycentric position of the cell in C at every second. Numbers show the tracking order. E, imaging of directional cell migration on the inner vascular surface. The yellow line represents an outline of the cancer cell. White arrowheads show red blood cells with a comet-like configuration. F, trajectory of the barycentric position of the cell in E at every second. G, cells in E superimposed for 16–17 s and 27–28 s. Yellow lines show outlines of cancer cells. Red arrowheads represent lamellipodia-like structures. H, traces of blue, purple, and orange squares, as shown with arrowheads in A, C, and E. Numbers show the tracking order. I, MSD plots of QDs on membranes of cells in the bloodstream (blue), on the inner vascular surface without directional migration (purple), and on the inner vascular surface with migration (orange), D = diffusion constant. Error bars indicate ± S.E. Blue data, n = 88 (22 trajectories/cell × 4 cells). Purple data, n = 115 (23 trajectories/cell × 5 cells). Orange data, n = 78 (26 trajectories/cell × 3 cells). Squares in A, C, and E show typical QDs on the edge of cells. Excitation, 532 nm; emission, 580 nm; exposure time, 0.2 s. Bars, 10 μm. Reprinted with permission from the Journal of Biological Chemistry , copyright 2009.

Figure 6

Schematic representations of CTX-enabled nanoparticles (NPCs) inhibiting tumor cell invasion and summary of MMP-2 and cell invasion inhibition data from. a) Surface chemistry of NPC conjugate. b) NPC binding to lipid rafts of glioma cells containing MMP-2 and select ion channels. c) Functional inhibition of NPC, free CTX, and NP on MMP-2 in the presence of gelatin. Comparable inhibition by CTX and NPC indicates retention of catalytic activity of CTX bound to NPC. d) TEM images showing increased membrane uptake subsequent to NPC binding. Scale bars represent 5 μm and 200 nm for whole cell (first row) and high magnification imaging (second row), respectively. White and black arrows identify NPC and endosomes, respectively. e) Quantitative assessment matrigel cell invasion post-treatment. f) Confocal differential interference contrast (DIC) and confocal fluorescence imaging, showing the morphological changes of C6 cells exposed to NPC (scale bar: 20 μm). Reproduced with permission from Wiley-VCH Verlag GmbH & Co. KGa: Small Copyright 2009.