[Cell Adhesion & Migration 3:3, 275-277; July/August/September 2009]; ©2009 Landes Bioscience
Fast growing malignant cancers represent a major thera-
peutic challenge. Basic cancer research has concentrated efforts
to determine the mechanisms underlying cancer initiation and
progression and reveal candidate targets for future therapeutic
treatment of cancer patients. With known roles in fundamental
processes required for proper development and function of the
nervous system, L1-CAMs have been recently identified as key
players in cancer biology. In particular L1 has been implicated
in cancer invasiveness and metastasis, and has been pursued as a
powerful prognostic factor, indicating poor outcome for patients.
Interestingly, L1 has been shown to be important for the survival
of cancer stem cells, which are thought to be the source of cancer
recurrence. The newly recognized roles for L1CAMs in cancer
prompt a search for alternative therapeutic approaches. Despite
the promising advances in cancer basic research, a better under-
standing of the molecular mechanisms dictating L1-mediated
signaling is needed for the development of effective therapeutic
treatment for cancer patients.
A major obstacle in oncology is the early diagnosis and curative
therapeutic intervention of locally invasive cancers that rapidly
disseminate from the primary tumor to form metastases. The stan-
dard treatment for malignant tumors consists of surgical removal
of the tumor mass followed by chemo- and radiotherapy in order
to eradicate the remaining cancer cells. Despite such aggressive
intervention, a population of resistant cancer cells often remains
intact and is thought to be the source of cancer recurrence.
During the past decades, cancer basic research has focused on
determining the molecular mechanisms underlying cancer initia-
tion and progression that can provide a basis for the development
of new and effective therapeutic treatments for cancer patients. An
important finding was the discovery that cancer onset and devel-
opment are often associated with alterations in the expression of
cell adhesion molecules, which are likely to stimulate tumor cell
invasiveness by signaling mechanisms that enhance cell migration.1
The L1 family of neural cell adhesion molecules (L1-CAMs), which
is comprised of four structurally related transmembrane proteins
L1, CHL1, NrCAM and neurofascin (Fig. 1), is now in the spot-
light of cancer research due to their upregulation in certain human
tumors. L1-CAMs are transmembrane molecules of the immuno-
globulin superfamily, characterized by an extracellular region of six
immunoglobulin-like domains and four to five fibronectin type
III repeats, followed by a highly conserved cytoplasmic domain,
which is reversibly linked to the cell cytoskeleton through binding
to ankyrin and ERM proteins (ezrin-radixin-moesin).2 Its multi-
domain structure allows complex heterophilic interactions with
diverse cell receptors, although homophilic interactions also have a
crucial role in L1-CAMs mediated signaling.
A wealth of studies has revealed L1-CAMs as pivotal components
for proper development of the nervous system through regulation
of cell-cell interactions. L1-CAMs have critical roles in neuronal
migration and survival, axon outgrowth and fasciculation, synaptic
plasticity and regeneration after trauma.2 Neither CHL1 nor L1 is
present on mature astrocytes, oligodendroglia or endothelial blood
vessel cells in the brain, but CHL1 is upregulated in astrocytes upon
injury3 and is present on oligodendroglial precursors.4,5 During
neural development, L1 plays an important role in the migration
of dopaminergic neuronal cell groups in the mesencephalon and
diencephalon.6 In the cerebellum, L1 is required for the inward
migration of granule neurons from the external granular layer
and cooperates with NrCAM in regulating neuronal positioning.2
Similarly, CHL1 controls area-specific migration and positioning
of deep layer cortical neurons in the neocortex.7 In addition to
its role in neuronal precursor positioning, L1 plays a crucial role
in axon guidance, which is governed by repellent and attractive
response mechanisms directed by Ephrins and Semaphorins and
their receptors (Ephs, Neuropilins, Plexins).2 The importance of
L1-CAMs in the development and function of the nervous system
is exemplified by developmental neuropsychiatric disorders that
are associated with mutation or genetic polymorphisms in genes
encoding L1 (X-linked mental retardation) and CHL1 (low IQ,
speech and motor delay). Polymorphisms in L1 and CHL1 genes
are also associated with schizophrenia, and NrCAM gene polymor-
phisms are linked to autism in some populations.2
Recent studies have described upregulation of L1 in a variety
of tumor types. Overexpression of L1 correlates with tumor
progression and metastasis in certain human gliomas,8 melanoma,9
*Correspondence to: Patricia F. Maness; Department of Biochemistry and
Biophysics; University of North Carolina; Genetic Medicine Research Building,
Suite 3020; Chapel Hill, NC 27599-7260 USA; Email: firstname.lastname@example.org
Submitted: 11/19/08; Accepted: 04/07/09
Previously published online as a Cell Adhesion & Migration E-publication:
Commentary & View
L1 cell adhesion molecules as regulators of tumor cell invasiveness
Priscila F. Siesser and Patricia F. Maness*
Department of Biochemistry and Biophysics; University of North Carolina; Chapel Hill; NC USA
Key words: L1CAMs, cancer, metastasis, axon guidance, cancer stem cell, migration, invasion
www.landesbioscience.comCell Adhesion & Migration275
276 Cell Adhesion & Migration2009; Vol. 3 Issue 3
ovarian10 and colon carcinomas.11-13 Interestingly, L1
was found to be present only in cells at the invasive front
of colon cancers but not in the tumor mass.12 L1 is also
associated with micrometastasis to both lymph nodes and
bone marrow in patients bearing other cancers, suggesting
a potential role in early metastatic spread.11 L1 has now
been pursued as both a biomarker and a powerful prog-
nostic factor, indicative of poor outcome for patients as
observed for epithelial ovarian carcinoma10 and colorectal
cancer.11 More recently, L1 has been shown to be over-
expressed in a small fraction of glioma cells, termed
glioma stem cells, which are capable of self-renewal and
generate the diverse cells that comprise the tumor.14 First
characterized in acute myeloid leukemia,15 cancer stem
cells have been recently described in a variety of solid
tumors, including breast cancer, lung cancer and gastro-
intestinal tumors.16 In gliomas, L1 expression was shown
to be required for maintaining the growth and survival of
glioma stem cells.14 These findings suggest that L1 may
be implicated not only in cancer invasiveness but also in
cancer survival. It will be important to determine if L1 is
also upregulated in other cancer stem cells as well as to
define the role of L1-mediated signaling in other cancers.
Although not extensively investigated, NrCAM has also
been shown to be overexpressed in glioblastoma cell
lines and several cases of high grade astrocytoma17 and
ependymomas.18 Studies are needed to address whether CHL1 and
neurofascin play analogous roles in cancer onset and progression.
The molecular mechanisms of L1-mediated signaling that
govern the migration of neuronal precursors and guidance of axons
during the development of the nervous system may also be used by
cancer cells to facilitate invasion and cancer progression. Integrins
are well-characterized cooperative partners for L1-CAMs, and
signal transduction pathways activated by this complex are known
to promote cell adhesion and directional motility. L1/integrin-
mediated signaling may converge with growth factor signaling
networks to promote motility. Like L1, CHL1 cooperates with
integrins to stimulate migration. All L1-CAMs reversibly engage
the actin cytoskeleton through a conserved motif FIGQ/AY in
the cytoplasmic domain that contains a crucial tyrosine residue
required for binding the spectrin adaptor ankyrin. Phosphorylation
of the FIGQY tyrosine decreases ankyrin binding, whereas dephos-
phorylation promotes L1-ankyrin interaction. Dynamic adhesive
interactions controlled by phosphorylation/dephosphorylation
of the ankyrin motif in L1 family members may enable a cell
to cyclically attach and detach from the ECM substrate or from
neighboring cells, thus facilitating migration.1 Another way L1
promotes cell migration is by stimulating endocytosis of integ-
rins, reducing cell adhesion to the extracellular matrix.19 Thus,
it is reasonable to speculate that upregulation of L1 in cancer
may result in increased L1-mediated signaling and, consequently,
increased cell migration.
L1-CAMs are cleaved by metalloproteases, releasing functionally
active ectodomain fragments that are laid down as “tracks” on the
extracellular matrix (ECM). These fragments can cause autocrine
activation of signal transduction pathways, promoting cell migra-
tion through heterophilic binding to integrins.20 Specifically, L1
is cleaved constitutively or inducibly by the ADAM family metal-
loproteases (a disintegrin and metalloprotease) ADAM10 and
ADAM17, which stimulates cell migration and neurite outgrowth
during brain development.20,21 In colon cancer, L1 colocalizes with
ADAM 10 at the invasive front of the tumor tissue, suggesting that
L1 shedding may play a role in cancer invasiveness.12 Similarly,
CHL1 is shed by ADAM8, which was reported to promote cell
migration and invasive activity of glioma cells in vitro and is
highly expressed in human brain tumors including glioblastoma
multiforme, correlating with invasiveness in vivo.22 Furthermore,
NrCAM, found in pancreatic, renal and colon cancers, is subject to
ectodomain shedding,23 but its function in regulating cell migra-
tion or invasion has not yet been studied.
Given the newly recognized roles of L1 in tumor progression,
a growing body of experimental studies has explored novel thera-
peutic approaches targeting L1-CAMs. Antibody-based therapeutic
strategies are being pursued to functionally inhibit homophilic and
heterophilic interactions of cell adhesion molecules to suppress
tumor invasive motility. L1 monoclonal antibodies reduce in vivo
growth of human ovarian and colon carcinoma cells in mouse
xenograft models.13,24,25 L1 targeting using lentiviral-mediated
short hairpin RNA (shRNA) interference decreases growth and
survival of glioma stem cells in vitro, suppresses tumor growth, and
increases survival of tumor-bearing animals.14 These findings raise
the possibility that L1 represents a cancer stem cell-specific thera-
peutic target for improving the treatment of malignant gliomas and
other brain tumors. Cancer stem cells represent a potential target
L1-CAMs in cancer
Figure 1. L1-CAMs: All have 6 Ig domains and 4–5 FN domains. The 186 kD
Neurofascin isoform has a mucin-like Pro/Ala/Thr-rich (PAT) domain, while the 155
kD has only the 4 FN domains. RGD and DGEA motifs interact with integrins, while
the FIGQ/AY motif binds to ankyrin. ERM binding sites are indicated. The RSLE motif
in L1 recruits AP2/clathrin adaptor for endocytosis.
L1-CAMs in cancer
14. Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, et al. Targeting cancer
stem cells through L1CAM suppresses glioma growth. Cancer Res 2008; 68:6043-8.
15. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell
initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature
16. Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma 2005; 52:435-40.
17. Sehgal A, Boynton AL, Young RF, Vermeulen SS, Yonemura KS, Kohler EP, et al. Cell
adhesion molecule Nr-CAM is overexpressed in human brain tumors. Int J Cancer 1998;
18. Lukashova-v Zangen I, Kneitz S, Monoranu CM, Rutkowski S, Hinkes B, Vince GH, et al.
Ependymoma gene expression profiles associated with histological subtype, proliferation
and patient survival. Acta Neuropathol 2007; 113:325-37.
19. Panicker AK, Buhusi M, Erickson A, Maness PF. Endocytosis of beta1 integrins is an
early event in migration promoted by the cell adhesion molecule L1. Exp Cell Res 2006;
20. Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S, et al.
Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine
binding to integrins. J Cell Biol 2001; 155:661-73.
21. Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, et al. L1 is
sequentially processed by two differently activated metalloproteases and presenilin/gam-
ma-secretase and regulates neural cell adhesion, cell migration and neurite outgrowth.
Mol Cell Biol 2005; 25:9040-53.
22. Wildeboer D, Naus S, Amy Sang QX, Bartsch JW, Pagenstecher A. Metalloproteinase
disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain
tumors and their expression levels and activities are associated with invasiveness. J
Neuropathol Exp Neurol 2006; 65:516-27.
23. Conacci-Sorrell M, Kaplan A, Raveh S, Gavert N, Sakurai T, Ben-Ze’ev A. The shed
ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell trans-
formation. Cancer Res 2005; 65:11605-12.
24. Arlt MJ, Novak-Hofer I, Gast D, Gschwend V, Moldenhauer G, Grunberg J, et al.
Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovar-
ian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody
treatment. Cancer Res 2006; 66:936-43.
25. Knogler K, Grunberg J, Zimmermann K, Cohrs S, Honer M, Ametamey S, et al.
Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion
molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis. Clin
Cancer Res 2007; 13:603-11.
26. Hart LS, El-Deiry WS. Invincible, but not invisible: imaging approaches toward in vivo
detection of cancer stem cells. J Clin Oncol 2008; 26:2901-10.
27. Herman JG, Meadows GG. Increased class 3 semaphorin expression modulates the
invasive and adhesive properties of prostate cancer cells. Int J Oncol 2007; 30:1231-8.
28. Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, Mercurio AM.
Competing autocrine pathways involving alternative neuropilin-1 ligands regulate
chemotaxis of carcinoma cells. Cancer Res 2003; 63:5230-3.
29. Muller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, et al. Association
of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int J
Cancer 2007; 121:2421-33.
30. Nguyen QD, Rodrigues S, Rodrigue CM, Rivat C, Grijelmo C, Bruyneel E, et al.
Inhibition of vascular endothelial growth factor (VEGF)-165 and semaphorin 3A-mediated
cellular invasion and tumor growth by the VEGF signaling inhibitor ZD4190 in human
colon cancer cells and xenografts. Mol Cancer Ther 2006; 5:2070-7.
for future treatment of different cancer as these cells are believed to
be responsible for cancer recurrence.26 Promoting cancer stem cell
differentiation by drug treatment could potentially reduce stem
cells properties of self-renewal and proliferation, leading to inhibi-
tion of tumor growth.
Inhibitors of metalloproteases that block L1-CAM shed-
ding represent a potentially novel approach to curtailing tumor
invasiveness. Chemical inhibitors of ADAMS are appealing for
glioma therapy due to their diffusability, which circumvents
blood-brain barrier limitations. Another novel approach involves
the secreted axon repellent protein, Semaphorin 3A (Sema3A).
L1-CAMs serve as co-receptors for Sema3A by cis binding in the
plasma membrane to Neuropilin-1, important for repellent axon
guidance.2 Interestingly, Sema3A inhibits invasiveness of prostate
cancer cells27 and migration and spreading of breast cancer cells
in in vitro assays,28 and thus may also be mediated by L1-CAMs.
Such an approach could be potentially useful in mitigating inva-
sion of cancer cells in gliomas and other tumors that are known to
express L1 and Neuropilins. However, effective strategies for some
types of cancer can promote cancer progression in other types. For
example, Sema3A has been shown to contribute to the progression
of pancreatic cancer29 and colon cancer.30 Thus, it is imperative
that the molecular mechanisms underlying L1-mediated signaling
are understood in a tissue specific manner. Despite the promising
advances in cancer basic research, much more research is needed to
better design strategies for cancer therapy.
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family: signaling transducers of axon guidance and neuronal migration. Nat Neurosci
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of CHL1 by glial cells in response to optic nerve injury and intravitreal application of
fibroblast growth factor-2. J Neurosci Res 2003; 71:835-43.
4. Holm J, Hillenbrand R, Steuber V, Bartsch U, Moos M, Lubbert H, et al. Structural
features of a close homologue of L1 (CHL1) in the mouse: a new member of the L1
family of neural recognition molecules. Eur J Neurosci 1996; 8:1613-29.
5. Hillenbrand R, Molthagen M, Montag D, Schachner M. The close homologue of the
neural adhesion molecule L1 (CHL1): patterns of expression and promotion of neurite
outgrowth by heterophilic interactions. Eur J Neurosci 1999; 11:813-26.
6. Demyanenko GP, Shibata Y, Maness PF. Altered distribution of dopaminergic neurons
in the brain of L1 null mice. Brain Res Dev Brain Res 2001; 126:21-30.
7. Demyanenko GP, Schachner M, Anton E, Schmid R, Feng G, Sanes J, Maness PF. Close
homolog of L1 modulates area-specific neuronal positioning and dendrite orientation in
the cerebral cortex. Neuron 2004; 44:423-37.
8. Tsuzuki T, Izumoto S, Ohnishi T, Hiraga S, Arita N, Hayakawa T. Neural cell adhesion
molecule L1 in gliomas: correlation with TGFbeta and p53. J Clin Pathol 1998; 51:13-7.
9. Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, Feinstein E, Einat P, Ben-Ze’ev A.
Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon
cancer and its expression enhances motility and confers tumorigenesis. Genes Dev 2002;
10. Zecchini S, Bianchi M, Colombo N, Fasani R, Goisis G, Casadio C, et al. The differen-
tial role of L1 in ovarian carcinoma and normal ovarian surface epithelium. Cancer Res
11. Kaifi JT, Reichelt U, Quaas A, Schurr PG, Wachowiak R, Yekebas EF, et al. L1 is associ-
ated with micrometastatic spread and poor outcome in colorectal cancer. Mod Pathol
12. Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T, Ben-Ze’ev A. L1,
a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive
front of colon cancers. J Cell Biol 2005; 168:633-42.
13. Gast D, Riedle S, Issa Y, Pfeifer M, Beckhove P, Sanderson MP, et al. The cytoplasmic
part of L1-CAM controls growth and gene expression in human tumors that is reversed
by therapeutic antibodies. Oncogene 2008; 27:1281-9.
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