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ATOMIC FORCE MICROSCOPY

A tip for diagnosing cancer

Stiffness measurements of tumour biopsies and single cells show unique fingerprints that identify the different
stages of cancer.

Normal

STOP

Normal tissue

0.10
0.08
0.06
0.04
0.02
0.00

Elasticity profile for

normal breast tissue

0 2 4 6 8 10 12 14 16 18 20
Stiffness (kPa)

Cancer
Breast tissue

STOP

Invasive cancer

Suspected tissue

Frequency count

he development of a variety of diseases

can be linked to changes in the
mechanical properties of living cells.
This includes diseases where mechanical
changes are clearly observable in a patient
such as with muscular dystrophies1, and
diseases where changes can only be observed
using experimental techniques such as with
cancers2. Over the past few years, atomic
force microscopy (AFM) has been used
to measure the mechanical properties of
cells, and the technique has revealed that
cancerous cells are softer than normal
cells2. Furthermore, the method can also
differentiate cancerous cells from nonmalignant and less-differentiated cancer
cells2. Yet, few clinicians consider this a
viable method for detecting cancerous
changes because tumours are structurally
complex and have heterogeneous properties.
Moreover, many researchers question the
relevance of elasticity measurements of
single cells because these are done in the
absence of a natural environment.
Writing in Nature Nanotechnology,
Roderick Lim and colleagues3 now show
that AFM measurements of the stiffness
of human breast biopsies reveal unique
mechanical fingerprints that help define
the stages of cancer progression. Highresolution stiffness mapping shows that
in addition to matrix stiffening, tumour
progression is due to softening of the
tumour cells.
With the aid of ultrasound imaging,
the researchers who are based at the
University of Basel and the Friedrich
Miescher Institute for Biomedical
Research obtained breast biopsies
from patients with suspicious lesions.
The biopsies, which were kept in buffer to
prevent degradation, were immobilized
on a plastic dish and indented with
an atomic force microscope under
physiological conditions. The stiffness of
the biopsy was determined from load force
versus indentation curves. The resulting
relationship between a load force and
an indentation depth was found to be
characteristic and specific for tissues from
normal, benign and cancerous tissue.

Frequency count

Magorzata Lekka

0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00

Elasticity profile for

cancerous breast tissue

0 2 4 6 8 10 12 14 16 18 20
Stiffness (kPa)

Figure 1 | Potential use of AFM in breast cancer diagnosis. The diagnosis of breast cancer at present
relies on histological staining (left; scale bar, 50m). Histological staining classifies biopsies into three
categories: no cancer (normal tissue), clearly visible cancer changes and suspected tissue that needs
to be examined further (middle). Atomic force microscopy can provide a mechanical fingerprint of
a suspected sample and help classify the tissue at a single-cell level (right). Histological image and
stiffness distribution graphs reproduced from ref.3.

Cancer-related changes in the

mechanical properties of cells were
previously thought to be limited to matrix
stiffening 4. However, Lim and colleagues
show that the progression of cancer is also
accompanied by a significant softening
of tumour cells compared with their
normal counterparts. For both normal
and benign tissues, the researchers found
uniform stiffness distributions. However,
Youngs modulus of benign tissues ranged
from 1.9kPa to 3.7kPa, which is higher
than normal tissues (1.1kPa to 1.8kPa).
Youngs modulus is a measure of the
stiffness of a material and, it is used to
compare the stiffness of the different
tissue samples. What causes the observed
increase in stiffness and how this effect
contributes to tumour progression remains
unclear. However, recent studies have
suggested that it might be related to a
larger density of collagen in mammary
tissues5,6, which seems to be confirmed by
direct measurements of tissue stiffening in
premalignant tissue3.

NATURE NANOTECHNOLOGY | VOL 7 | NOVEMBER 2012 | www.nature.com/naturenanotechnology

2012 Macmillan Publishers Limited. All rights reserved

For invasive cancers, Lim and co-workers

found that such tissue can be recognized
by a characteristic profile with a dominant
peak between 0.3 and 0.8kPa, which is in
agreement with measurements on single
cells6. The lesions also showed a second (or
even third) peak, suggesting a stiffer material.
This stiffening was observed at the periphery
of the biopsies, and may correlate with what
can be detected with physical examinations
of patients with cancers. Significantly, the
results obtained from human biopsies
were confirmed with systematic studies on
transgenic micemodels.
It is worth noting that the mechanical
fingerprints observed by the researchers
are characteristic for breast tissue. It is
possible that other cancers could exhibit
similar or different mechanical behaviours
(that is, Youngs modulus distributions
could have similar or different forms).
Furthermore, because tissue sections from
solid tumours are highly complex and can
exhibit molecular, cellular and architectural
alterations7,8, a deeper knowledge of cancer691

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related changes is still required when
diagnosing cancer.
Although questions remain about the
cause of the observed changes in stiffness,
the work of Lim and colleagues could have
significant practical implications because all
that is required for reliable measurements is
a standard biopsy procedure, and diagnosis
can be performed in parallel with other
more commonly used techniques. Moreover,
because the optical microscope used in
conjunction with the AFM measurements
cannot recognize cancerous regions in
unstained tissue biopsies, the AFM method
is not biased by direct observation, and has
properties of a blind assay.

Breast cancer diagnosis begins at

present with mammography imaging,
which provides sufficient resolution to
detect cancers in most of the women
examined. However, the technique can
sometimes be inconclusive. In such
cases, a biopsy is normally collected for
histological staining (Fig.1). The stained
tissue sections are then grouped as normal
(healthy), cancerous and undefined.
The mechanical fingerprinting method
developed by the Swiss team3 offers an
additional step to tissue classification,
which could detect cancerous cells that
might be overlooked during histochemical
analysis. It is a promising tool that can

help patients and doctors obtain a more

reliablediagnosis.

Magorzata Lekka is in the Department of Applied

Spectroscopy at the Institute of Nuclear Physics,
Polish Academy of Sciences, Radzikowskiego 152,
31-342 Krakw, Poland.
e-mail: Malgorzata.Lekka@ifj.edu.pl
References
1.
2.
3.
4.
5.
6.
7.
8.

Bushby, K. etal. Curr. Pediatrics 15, 292300 (2005).

Lekka, M. etal. Arch. Biochem. Biophys. 518, 151156 (2012).
Plodinec, M. etal. Nature Nanotech. 7, 757765 (2012).
Levental, K.R. etal. Cell 139, 891906 (2009).
Provenzano, P. etal. BMC Med. 6, 11 (2008).
Prabhune, M. etal. Micron 43, 12671272 (2012).
Moore, N. etal. Phys. Biol. 8, 010302 (2011).
Kumar, S. & Weaver, V.M. Cancer Metast. Rev. 28, 113127 (2009).

SPIN INJECTION

Graphene wins the match

A single layer of graphene can be used as a tunnel barrier for spin injection in silicon with several advantages over
other materials that have previously been used.

Hanan Dery

n addition to their electric charge,

electrons carry an intrinsic angular
momentum called spin. Measurement
of the spin component along an arbitrary
direction shows a binary-valued result
associated with a spin-up or a spin-down
electron. The measured value, /2, reflects
the quanta of angular momentum in
quantum mechanics where is thereduced
Planck constant. The spin degree-offreedom is therefore a natural candidate to
represent 0 and 1 in digital electronics.
Researchers conjecture that using spin
and charge in the same circuit will allow
more and more computational power
a

to be packed into smaller and smaller

areas1,2. Because charge-based fieldeffect transistors are rapidly approaching
their physical limits, the spincharge
computation scheme has recently become
an active research frontier. Such a quantum
leap in the architecture of logic circuits,
however, starts with basic bits-and-pieces of
spin injection, manipulation and detection
inside a spintronic device36. Writing in
Nature Nanotechnology, Vant Erve and
colleagues report on the demonstration of
robust room-temperature spin injection
using a graphene tunnel barrier between a
reservoir of spin-polarized electrons and a
b

silicon channel7. The results are particularly

noteworthy as silicon is the material used
in the present electronic devices, which
could, in principle, be upgraded with
added functionalities provided by the
electronspin.
Electrical spin-injection from a
ferromagnetic metal (reservoir of spinpolarized electrons) to a semiconductor
is not as trivial as passing current across
the junction between these materials.
The problem is that the injected spin
polarization is absorbed back into the
metallic reservoir if the contact is a
non-rectifying junction of low resistance
c

e
xid

O
Oh

ne

phe

Gra

mic

FM

Semiconductor

FM

Semiconductor

FM

Semiconductor

Figure 1 | Spin injection from a ferromagnetic metal (FM) to a semiconductor. a, The ultralow resistive junction (ohmic contact) enables a strong
charge-current signal (green arrow) but it inhibits the transfer of spin polarization to the semiconductor (see main text). The blue arrow indicates the
magnetization(M). b, The insertion of a highly-resistive oxide tunnel barrier ensures that the injected spin polarization is not absorbed back into the reservoir.
However, the number of spin-polarized electrons that tunnel through the barrier is relatively small and can be readily masked by a background of spinunpolarized electrons. The illustrated charge-traps inside the oxide cause a delay in the injection process. c, Insertion of a tunnel barrier made of a single-layer
graphene flake overcomes all these problems.
692

NATURE NANOTECHNOLOGY | VOL 7 | NOVEMBER 2012 | www.nature.com/naturenanotechnology

2012 Macmillan Publishers Limited. All rights reserved