Cell, Vol. 100, 57–
Cell Press
The Hallmarks of Cancer Review
evolve progressively from normalcy via a series of pre-Douglas
Hanahan* and Robert A. Weinberg†
*Department of Biochemistry and Biophysics and malignant
states into invasive cancers (Foulds, 1954).
These observations have been rendered more con-Hormone
Research Institute
University of California at San Francisco crete by a large body
of work indicating that the ge-
nomes of tumor cells are invariably altered at multipleSan
Francisco, California 94143
†Whitehead Institute for Biomedical Research and sites, having
suffered disruption through lesions as sub-
tle as point mutations and as obvious as changes inDepartment
of Biology
Massachusetts Institute of Technology chromosome complement
(e.g., Kinzler and Vogelstein,
1996). Transformation of cultured cells is itself aCambridge,
Massachusetts 02142
multistep process: rodent cells require at least two intro-
duced genetic changes before they acquire tumorigenic
competence, while their human counterparts are moreAfter a
quarter century of rapid advances, cancer re-
difficult to transform (Hahn et al., 1999). Transgenicsearch has

generated a rich and complex body of knowl-
models of tumorigenesis have repeatedly supported theedge,
revealing cancer to be a disease involving dy-
conclusion that tumorigenesis in mice involves multiplenamic
changes in the genome. The foundation has been
rate-limiting steps (Bergers et al., 1998; see Oncogene,set in the
discovery of mutations that produce onco-
1999, R. DePinho and T. E. Jacks, volume 18[38], pp.genes
with dominant gain of function and tumor sup-
5248–5362). Taken together, observations of humanpressor
genes with recessive loss of function; both
cancers and animal models argue that tumor develop-classes of
cancer genes have been identified through
ment proceeds via a process formally analogous to Dar-their
alteration in human and animal cancer cells and
winian evolution, in which a succession of geneticby their
elicitation of cancer phenotypes in experimental
changes, each conferring one or another type of growthmodels
(Bishop and Weinberg, 1996).
advantage, leads to the progressive conversion of nor-Some
would argue that the search for the origin and
mal human cells into cancer cells (Foulds, 1954;
Nowell,treatment of this disease will continue over the next
1976).quarter century in much the same manner as it has in
the recent past, by adding further layers of complexity
to a scientific literature that is already complex almost An
Enumeration of the Traits
beyond measure. But we anticipate otherwise: those The
barriers to development of cancer are embodied
researching the cancer problem will be practicing a dra- in a
teleology: cancer cells have defects in regulatory
matically different type of science than we have experi- circuits
that govern normal cell proliferation and homeo-
enced over the past 25 years. Surely much of this change stasis.
There are more than 100 distinct types of cancer,

will be apparent at the technical level. But ultimately, and
subtypes of tumors can be found within specific
the more fundamental change will be conceptual. organs. This
complexity provokes a number of ques-
We foresee cancer research developing into a logical tions. How
many distinct regulatory circuits within each
science, where the complexities of the disease, de- type of
target cell must be disrupted in order for such
scribed in the laboratory and clinic, will become under- a cell to
become cancerous? Does the same set of
standable in terms of a small number of underlying prin-
cellular regulatory circuits suffer disruption in the cells
ciples. Some of these principles are even now in the of the
disparate neoplasms arising in the human body?
midst of being codified. We discuss one set of them in Which of
these circuits operate on a cell-autonomous
the present essay: rules that govern the transformation basis,
and which are coupled to the signals that cells
of normal human cells into malignant cancers. We sug- receive
from their surrounding microenvironment within
gest that research over the past decades has revealed a tissue?
Can the large and diverse collection of cancer-
a small number of molecular, biochemical, and cellular
associated genes be tied to the operations of a small
traits—acquired capabilities—shared by most and per- group of
regulatory circuits?
haps all types of human cancer. Our faith in such simplifi- We
suggest that the vast catalog of cancer cell geno-
cation derives directly from the teachings of cell biology types
is a manifestation of six essential alterations in cell
that virtually all mammalian cells carry a similar molecu-
physiology that collectively dictate malignant growth
lar machinery regulating their proliferation, differentia- (Figure
1): self-sufficiency in growth signals, insensitivity
tion, and death. to growth-inhibitory (antigrowth) signals,

evasion of pro-
Several lines of evidence indicate that tumorigenesis grammed
cell death (apoptosis), limitless replicative
in humans is a multistep process and that these steps potential,
sustained angiogenesis, and tissue invasion
reflect genetic alterations that drive the progressive and
metastasis. Each of these physiologic changes—
transformation of normal human cells into highly malig- novel
capabilities acquired during tumor development—
nant derivatives. Many types of cancers are diagnosed
represents the successful breaching of an anticancer
in the human population with an age-dependent inci- defense
mechanism hardwired into cells and tissues.
dence implicating four to seven rate-limiting, stochastic We
propose that these six capabilities are shared in
events (Renan, 1993). Pathological analyses of a number
common by most and perhaps all types of human tu-
of organ sites reveal lesions that appear to represent mors. This
multiplicity of defenses may explain why can-
cer is relatively rare during an average human lifetime.the
intermediate steps in a process through which cells
Cell
58
Acquired GS autonomy was the first of the six capabili-
ties to be clearly defined by cancer researchers, in large
part because of the prevalence of dominant oncogenes
that have been found to modulate it. Three common
molecular strategies for achieving autonomy are evi-
dent, involving alteration of extracellular growth signals,
of transcellular transducers of those signals, or of intra-

cellular circuits that translate those signals into action.
While most soluble mitogenic growth factors (GFs) are
made by one cell type in order to stimulate proliferation
of another—the process of heterotypic signaling—many
cancer cells acquire the ability to synthesize GFs to
which they are responsive, creating a positive feedback
signaling loop often termed autocrine stimulation (Fedi
et al., 1997). Clearly, the manufacture of a GF by a cancer
cell obviates dependence on GFs from other cells within
the tissue. The production of PDGF (platelet-derived
growth factor) and TGFa (tumor growth factor a) by
glioblastomas and sarcomas, respectively, are two illus-
trative examples (Fedi et al., 1997).
The cell surface receptors that transduce growth-
stimulatory signals into the cell interior are themselves
targets of deregulation during tumor pathogenesis. GF
receptors, often carrying tyrosine kinase activities in
their cytoplasmic domains, are overexpressed in many
cancers. Receptor overexpression may enable the can-
cer cell to become hyperresponsive to ambient levelsFigure 1.
Acquired Capabilities of Cancer
of GF that normally would not trigger proliferation (FediWe
suggest that most if not all cancers have acquired the same set
et al., 1997). For example, the epidermal GF receptorof
functional capabilities during their development, albeit through
various mechanistic strategies. (EGF-R/erbB) is upregulated in
stomach, brain, and
breast tumors, while the HER2/neu receptor is overex-
pressed in stomach and mammary carcinomas (Slamon
et al., 1987; Yarden and Ullrich, 1988). Additionally, grossWe
describe each capability in turn below, illustrate with
overexpression of GF receptors can elicit ligand-inde-a few
examples its functional importance, and indicate
pendent signaling (DiFiore et al., 1987). Ligand-indepen-

strategies by which it is acquired in human cancers.
dent signaling can also be achieved through structural
alteration of receptors; for example, truncated versions
Acquired Capability: Self-Sufficiency
of the EGF receptor lacking much of its cytoplasmic
in Growth Signals
domain fire constitutively (Fedi et al., 1997).
Normal cells require mitogenic growth signals (GS) be- Cancer
cells can also switch the types of extracellular
fore they can move from a quiescent state into an active matrix
receptors (integrins) they express, favoring ones
proliferative state. These signals are transmitted into the that
transmit progrowth signals (Lukashev and Werb,
cell by transmembrane receptors that bind distinctive 1998;
Giancotti and Ruoslahti, 1999). These bifunctional,
classes of signaling molecules: diffusible growth fac-
heterodimeric cell surface receptors physically link cells
tors, extracellular matrix components, and cell-to-cell to
extracellular superstructures known as the extracellu-
adhesion/interaction molecules. To our knowledge, no lar
matrix (ECM). Successful binding to specific moieties
type of normal cell can proliferate in the absence of of the ECM
enables the integrin receptors to transduce
such stimulatory signals. Many of the oncogenes in the signals
into the cytoplasm that influence cell behavior,
cancer catalog act by mimicking normal growth signal- ranging
from quiescence in normal tissue to motility,
ing in one way or another. resistance to apoptosis, and entrance
into the active
Dependence on growth signaling is apparent when cell cycle.
Conversely, the failure of integrins to forge
propagating normal cells in culture, which typically pro- these

extracellular links can impair cell motility, induce
liferate only when supplied with appropriate diffusible
apoptosis, or cause cell cycle arrest (Giancotti and Ru-
mitogenic factors and a proper substratum for their inte- oslahti,
1999). Both ligand-activated GF receptors and
grins. Such behavior contrasts strongly with that of tu-
progrowth integrins engaged to extracellular matrix
mor cells, which invariably show a greatly reduced components
can activate the SOS-Ras-Raf-MAP kinase
dependence on exogenous growth stimulation. The con- pathway
(Aplin et al., 1998; Giancotti and Ruoslahti,
clusion is that tumor cells generate many of their own 1999).
growth signals, thereby reducing their dependence on The most
complex mechanisms of acquired GS auton-
stimulation from their normal tissue microenvironment. omy
derive from alterations in components of the down-
This liberation from dependence on exogenously de- stream
cytoplasmic circuitry that receives and pro-
rived signals disrupts a critically important homeostatic cesses
the signals emitted by ligand-activated GF
mechanism that normally operates to ensure a proper receptors
and integrins. The SOS-Ras-Raf-MAPK cas-
cade plays a central role here. In about 25% of humanbehavior
of the various cell types within a tissue.
Review
59
Figure 2. The Emergent Integrated Circuit of the Cell
Progress in dissecting signaling pathways has begun to lay out a
circuitry that will likely mimic electronic integrated circuits in
complexity

and finesse, where transistors are replaced by proteins (e.g.,
kinases and phosphatases) and the electrons by phosphates and
lipids, among
others. In addition to the prototypical growth signaling circuit
centered around Ras and coupled to a spectrum of extracellular
cues, other
component circuits transmit antigrowth and differentiation
signals or mediate commands to live or die by apoptosis. As for
the genetic
reprogramming of this integrated circuit in cancer cells, some of
the genes known to be functionally altered are highlighted in
red.
tumors, Ras proteins are present in structurally altered multiple
cell biological effects. For example, the direct
interaction of the Ras protein with the survival-promot-forms
that enable them to release a flux of mitogenic
signals into cells, without ongoing stimulation by their ing PI3
kinase enables growth signals to concurrently
evoke survival signals within the cell (Downward, 1998).normal
upstream regulators (Medema and Bos, 1993).
We suspect that growth signaling pathways suffer While
acquisition of growth signaling autonomy by
cancer cells is conceptually satisfying, it is also tooderegulation
in all human tumors. Although this point
is hard to prove rigorously at present, the clues are simplistic.
We have traditionally explored tumor growth
by focusing our experimental attentions on the geneti-abundant
(Hunter, 1997). For example, in the best stud-
ied of tumors—human colon carcinomas—about half cally
deranged cancer cells (Figure 3, left panel). It is,
however, increasingly apparent that the growth deregu-of the

tumors bear mutant ras oncogenes (Kinzler and
Vogelstein, 1996). We suggest that the remaining colonic lation
within a tumor can only be explained once we
understand the contributions of the ancillary cells pres-tumors
carry defects in other components of the growth
signaling pathways that phenocopy ras oncogene acti- ent in a
tumor—the apparently normal bystanders such
as fibroblasts and endothelial cells—which must playvation.
The nature of these alternative, growth-stimulat-
ing mechanisms remains elusive. key roles in driving tumor cell
proliferation (Figure 3,
right panel). Within normal tissue, cells are largely in-Under
intensive study for two decades, the wiring
diagram of the growth signaling circuitry of the mamma-
structed to grow by their neighbors (paracrine signals)
or via systemic (endocrine) signals. Cell-to-cell growthlian cell
is coming into focus (Figure 2). New downstream
effector pathways that radiate from the central SOS- signaling is
likely to operate in the vast majority of human
tumors as well; virtually all are composed of severalRas-Raf-
MAP kinase mitogenic cascade are being dis-
covered with some regularity (Hunter, 1997; Rommel distinct
cell types that appear to communicate via het-
erotypic signaling.and Hafen, 1998). This cascade is also linked
via a variety
of cross-talking connections with other pathways; these
Heterotypic signaling between the diverse cell types
within a tumor may ultimately prove to be as importantcross
connections enable extracellular signals to elicit

Cell
60
Figure 3. Tumors as Complex Tissues
The field of cancer research has largely been
guided by a reductionist focus on cancer cells
and the genes within them (left panel)—a fo-
cus that has produced an extraordinary body
of knowledge. Looking forward in time, we
believe that important new inroads will come
from regarding tumors as complex tissues in
which mutant cancer cells have conscripted
and subverted normal cell types to serve as
active collaborators in their neoplastic agenda
(right panel). The interactions between the
genetically altered malignant cells and these
supporting coconspirators will prove critical
to understanding cancer pathogenesis and to
the development of novel, effective therapies.
in explaining tumor cell proliferation as the cancer cell- the
components governing the transit of the cell through
the G1 phase of its growth cycle. Cells monitor theirautonomous
mechanisms enumerated above. For ex-
ample, we suspect that many of the growth signals driv-
external environment during this period and, on the ba-
sis of sensed signals, decide whether to proliferate, toing the
proliferation of carcinoma cells originate from
the stromal cell components of the tumor mass. While be
quiescent, or to enter into a postmitotic state. At the

molecular level, many and perhaps all antiproliferativedifficult
to validate at present, such thinking recasts the
logic of acquired GS autonomy: successful tumor cells signals
are funneled through the retinoblastoma protein
(pRb) and its two relatives, p107 and p130. When in aare those
that have acquired the ability to co-opt their
normal neighbors by inducing them to release abundant
hypophosphorylated state, pRb blocks proliferation by
sequestering and altering the function of E2F transcrip-fluxes of
growth-stimulating signals (Skobe and Fu-
senig, 1998). Indeed, in some tumors, these cooperating tion
factors that control the expression of banks of genes
essential for progression from G1 into S phase (Wein-cells may
eventually depart from normalcy, coevolving
with their malignant neighbors in order to sustain the berg,
1995).
Disruption of the pRb pathway liberates E2Fs andgrowth of the
latter (Kinzler and Vogelstein, 1998; Olumi
et al., 1999). Further, inflammatory cells attracted to sites thus
allows cell proliferation, rendering cells insensitive
to antigrowth factors that normally operate along thisof
neoplasia may promote (rather than eliminate) cancer
cells (Cordon-Cardo and Prives, 1999; Coussens et al., pathway
to block advance through the G1 phase of the
cell cycle. The effects of the soluble signaling molecule1999;
Hudson et al., 1999), another example of normal
cells conscripted to enhance tumor growth potential, TGFb are
the best documented, but we envision other
antigrowth factors will be found to signal through thisanother

means to acquire necessary capabilities.
pathway as well. TGFb acts in a number of ways, most
still elusive, to prevent the phosphorylation that inacti-Acquired
Capability: Insensitivity
to Antigrowth Signals vates pRb; in this fashion, TGFb blocks
advance through
G1. In some cell types, TGFb suppresses expressionWithin a
normal tissue, multiple antiproliferative signals
operate to maintain cellular quiescence and tissue ho- of the c-
myc gene, which regulates the G1 cell cycle
machinery in still unknown ways (Moses et al.,
1990).meostasis; these signals include both soluble growth
inhibitors and immobilized inhibitors embedded in the More
directly, TGFb causes synthesis of the p15INK4B and
p21 proteins, which block the cyclin:CDK
complexesextracellular matrix and on the surfaces of nearby
cells.
These growth-inhibitory signals, like their positively act-
responsible for pRb phosphorylation (Hannon and
Beach, 1994; Datto et al., 1997).ing counterparts, are received
by transmembrane cell
surface receptors coupled to intracellular signaling cir- The pRb
signaling circuit, as governed by TGFb and
other extrinsic factors, can be disrupted in a variety ofcuits.
Antigrowth signals can block proliferation by two dis- ways in
different types of human tumors (Fynan and
Reiss, 1993). Some lose TGFb responsiveness throughtinct
mechanisms. Cells may be forced out of the active
proliferative cycle into the quiescent (G0) state from

downregulation of their TGFb receptors, while others
display mutant, dysfunctional receptors (Fynan andwhich they
may reemerge on some future occasion
when extracellular signals permit. Alternatively, cells Reiss,
1993; Markowitz et al., 1995). The cytoplasmic
Smad4 protein, which transduces signals from ligand-may be
induced to permanently relinquish their prolifera-
tive potential by being induced to enter into postmitotic
activated TGFb receptors to downstream targets, may
be eliminated through mutation of its encoding genestates,
usually associated with acquisition of specific
differentiation-associated traits. (Schutte et al., 1996). The
locus encoding p15INK4B may be
deleted (Chin et al., 1998). Alternatively, the
immediateIncipient cancer cells must evade these antiprolifera-
tive signals if they are to prosper. Much of the circuitry
downstream target of its actions, CDK4, may become
unresponsive to the inhibitory actions of p15INK4B be-that
enables normal cells to respond to antigrowth sig-
nals is associated with the cell cycle clock, specifically cause of
mutations that create amino acid substitutions
Review
61
in its INK4A/B-interacting domain; the resulting cyclin in
virtually all cell types throughout the body. Once trig-
gered by a variety of physiologic signals, this programD:CDK4
complexes are then given a free hand to inacti-

vate pRb by hyperphosphorylation (Zuo et al., 1996). unfolds in
a precisely choreographed series of steps.
Cellular membranes are disrupted, the cytoplasmic andFinally,
functional pRb, the end target of this pathway,
may be lost through mutation of its gene. Alternatively, nuclear
skeletons are broken down, the cytosol is ex-
truded, the chromosomes are degraded, and the nu-in certain
DNA virus-induced tumors, notably cervical
carcinomas, pRb function is eliminated through seques- cleus is
fragmented, all in a span of 30–120 min. In the
end, the shriveled cell corpse is engulfed by nearby cellstration
by viral oncoproteins, such as the E7 oncoprotein
of human papillomavirus (Dyson et al., 1989). In addition, in a
tissue and disappears, typically within 24 hr (Wyllie
et al., 1980).cancer cells can also turn off expression of
integrins and
other cell adhesion molecules that send antigrowth sig- The
apoptotic machinery can be broadly divided into
two classes of components—sensors and effectors. Thenals,
favoring instead those that convey progrowth sig-
nals; these adherence-based antigrowth signals likely sensors
are responsible for monitoring the extracellular
and intracellular environment for conditions of
normalityimpinge on the pRb circuit as well. The bottom line is
that the antigrowth circuit converging onto Rb and the or
abnormality that influence whether a cell should live
or die. These signals regulate the second class of com-cell
division cycle is, one way or another, disrupted in

a majority of human cancers, defining the concept and ponents,
which function as effectors of apoptotic death.
The sentinels include cell surface receptors that binda purpose
of tumor suppressor loss in cancer.
Cell proliferation depends on more than an avoidance survival
or death factors. Examples of these ligand/
receptor pairs include survival signals conveyed by IGF-of
cytostatic antigrowth signals. Our tissues also con-
strain cell multiplication by instructing cells to enter irre-
1/IGF-2 through their receptor, IGF-1R, and by IL-3 and
its cognate receptor, IL-3R (Lotem and Sachs, 1996;versibly
into postmitotic, differentiated states, using di-
verse mechanisms that are incompletely understood; it Butt et
al., 1999). Death signals are conveyed by the
FAS ligand binding the FAS receptor and by TNFa bind-is
apparent that tumor cells use various strategies to
avoid this terminal differentiation. One strategy for ing TNF-R1
(Ashkenazi and Dixit, 1999). Intracellular
sensors monitor the cell’s well-being and activate theavoiding
differentiation directly involves the c-myc on-
cogene, which encodes a transcription factor. During death
pathway in response to detecting abnormalities,
including DNA damage, signaling imbalance provokednormal
development, the growth-stimulating action of
Myc, in association with another factor, Max, can be by
oncogene action, survival factor insufficiency, or hyp-
oxia (Evan and Littlewood, 1998). Further, the life of
mostsupplanted by alternative complexes of Max with a
group of Mad transcription factors; the Mad–Max com- cells is

in part maintained by cell–matrix and cell–cell
adherence-based survival signals whose abrogationplexes elicit
differentiation-inducing signals (Foley and
Eisenman, 1999). However, overexpression of the c-Myc elicits
apoptosis (Ishizaki et al., 1995; Giancotti and Ru-
oslahti, 1999). Both soluble and immobilized
apoptoticoncoprotein, as is seen in many tumors, can reverse
this
process, shifting the balance back to favor Myc–Max regulatory
signals likely reflect the needs of tissues to
maintain their constituent cells in appropriate architec-
complexes, thereby impairing differentiation and pro-
moting growth. During human colon carcinogenesis, in- tural
configurations.
Many of the signals that elicit apoptosis convergeactivation of
the APC/b-catenin pathway serves to block
the egress of enterocytes in the colonic crypts into a on the
mitochondria, which respond to proapoptotic
signals by releasing cytochrome C, a potent catalyst
ofdifferentiated, postmitotic state (Kinzler and Vogelstein,
1996). Analogously, during the generation of avian eryth-
apoptosis (Green and Reed, 1998). Members of the Bcl-2
family of proteins, whose members have either pro-roblastosis,
the erbA oncogene acts to prevent irrevers-
ible erythrocyte differentiation (Kahn et al., 1986). apoptotic
(Bax, Bak, Bid, Bim) or antiapoptotic (Bcl-2,
Bcl-XL, Bcl-W) function, act in part by governing mito-While
the components and interconnections between
the various antigrowth and differentiation-inducing sig-

chondrial death signaling through cytochrome C re-
lease. The p53 tumor suppressor protein can elicit apo-nals and
the core cell cycle machinery are still being
delineated, the existence of an antigrowth signaling cir- ptosis
by upregulating expression of proapoptotic Bax
in response to sensing DNA damage; Bax in turn stimu-cuitry is
clear (Figure 2), as is the necessity for its circum-
vention by developing cancers. lates mitochondria to release
cytochrome C.
The ultimate effectors of apoptosis include an array
of intracellular proteases termed caspases (ThornberryAcquired
Capability: Evading Apoptosis
and Lazebnik, 1998). Two “gatekeeper” caspases, 28The ability
of tumor cell populations to expand in number
and 29, are activated by death receptors such as FASis
determined not only by the rate of cell proliferation
or by the cytochrome C released from mitochondria,but also by
the rate of cell attrition. Programmed cell
respectively. These proximal caspases trigger the acti-death—
apoptosis—represents a major source of this
vation of a dozen or more effector caspases that
executeattrition. The evidence is mounting, principally from
the death program, through selective destruction of sub-studies
in mouse models and cultured cells, as well as
cellular structures and organelles, and of the genome.from
descriptive analyses of biopsied stages in human
The possibility that apoptosis serves as a barrier
tocarcinogenesis, that acquired resistance toward apo-
cancer was first raised in 1972, when Kerr, Wyllie, andptosis is
a hallmark of most and perhaps all types of
Currie described massive apoptosis in the cells populat-cancer.
ing rapidly growing, hormone-dependent tumors follow-

Observations accumulated over the past decade indi-
cate that the apoptotic program is present in latent form ing
hormone withdrawal (Kerr et al., 1972). The discovery
Cell
62
of the bcl-2 oncogene by its upregulation via chromo-
abnormalities, including hypoxia and oncogene hyper-
expression, are also funneled in part via p53 to the apo-somal
translocation in follicular lymphoma (reviewed in
ptotic machinery; these too are impaired at elicitingKorsmeyer,
1992) and its recognition as having anti-
apoptosis when p53 function is lost (Levine, 1997). Addi-
apoptotic activity (Vaux et al., 1988) opened up the in-
tionally, the PI3 kinase–AKT/PKB pathway, which trans-
vestigation of apoptosis in cancer at the molecular level.
mits antiapoptotic survival signals, is likely involved inWhen
coexpressed with a myc oncogene in transgenic
mitigating apoptosis in a substantial fraction of humanmice, the
bcl-2 gene was able to promote formation of
tumors. This survival signaling circuit can be activatedB cell
lymphomas by enhancing lymphocyte survival, not
by extracellular factors such as IGF-1/2 or IL-3 (Evanby further
stimulating their myc-induced proliferation
and Littlewood, 1998), by intracellular signals
emanating(Strasser et al., 1990); further, 50% of the infrequent
from Ras (Downward, 1998), or by loss of the pTENlymphomas
arising in bcl-2 single transgenic transgenic
tumor suppressor, a phospholipid phosphatase thatmice had
somatic translocations activating c-myc, con-
normally attenuates the AKT survival signal (Cantley
andfirming a selective pressure during lymphomagenesis

Neel, 1999). Recently, a mechanism for abrogating theto
upregulate both Bcl-2 and c-Myc (McDonnell and
FAS death signal has been revealed in a high
fractionKorsmeyer, 1991).
of lung and colon carcinoma cell lines: a nonsignalingFurther
insight into the myc-bcl-2 interaction emerged
decoy receptor for FAS ligand is upregulated, titratinglater from
studying the effects of a myc oncogene on
the death-inducing signal away from the FAS death re-
fibroblasts cultured in low serum. Widespread apoptosis
ceptor (Pitti et al., 1998). We expect that virtually allwas
induced in myc-expressing cells lacking serum; the
cancer cells harbor alterations that enable evasion ofconsequent
apoptosis could be abrogated by exoge-
apoptosis.nous survival factors (e.g., IGF-1), by forced
overexpres-
It is now possible to lay out a provisional apoptoticsion of Bcl-
2 or the related Bcl-XL protein, or by disrup-
signaling circuitry (Figure 2); while incomplete, it is evi-tion of
the FAS death signaling circuit (Hueber et al.,
dent that most regulatory and effector components are1997).
Collectively, the data indicate that a cell’s apo-
present in redundant form. This redundancy holds im-ptotic
program can be triggered by an overexpressed
portant implications for the development of novel
typesoncogene. Indeed, elimination of cells bearing activated
of antitumor therapy, since tumor cells that have lost
oncogenes by apoptosis may represent the primary
proapoptotic components are likely to retain other simi-
means by which such mutant cells are continually …

10-107
September 10, 2010
This case was prepared by Professors Deborah Ancona, MIT
Sloan School of Management and David Caldwell, Santa Clara
University, Leavey School of Business.
Copyright © 2010, Deborah Ancona and David Caldwell. This
work is licensed under the Creative Commons Attribution-
Noncommercial-No Derivative Works 3.0 Unported License. To
view a copy of this license visit
http://creativecommons.org/licenses/by-nc-nd/3.0/ or send a
letter to Creative Commons, 171 Second Street, Suite 300, San
Francisco, California, 94105, USA.
Chris Peterson at DSS Consulting
Deborah Ancona and David Caldwell
Late Thursday afternoon, Chris Peterson was reflecting on the
meeting she would have tomorrow
with her boss, Meg Cooke. The purpose of the meeting was to
give Meg an update on the status of the
integrated budget and planning system her team had been
working on over the last six months and
plans for the team to begin marketing this system and other new
DSS consulting services to clients.
Overall, Chris was quite pleased with the work her team had
done. The team had been formed as part
of a strategic change, including a somewhat controversial re-
organization at DSS. The changes and
new structure had created dissatisfaction and a fair amount of
anxiety among many of DSS’s
consultants, but Chris felt her team had overcome their concerns

to become a very effective group.
They had worked together well, avoided the conflicts that often
plague these kinds of teams, and
generally maintained a high level of motivation and satisfaction.
Most of all, Chris was proud of the
work her team had done. They had created a budget and
planning system that the team believed
would be embraced by DSS’s clients. The team had not gotten
much support from other groups at
DSS in developing the system, so team members had done much
of the technical work on their own
that would have normally been done by support people in the
company. Despite this, Chris was very
pleased with the system and looked forward to sharing her
team’s accomplishments with Meg.
DSS Consulting
DSS Consulting was formed in 1997 to provide administrative
support to small school districts
primarily in the mid-west and mountain west. The company was
founded by three retired school
district administrators to help small school districts that had
limited staff deal with difficult and
somewhat specialized administrative problems, such as
negotiating labor agreements or setting up
procurement systems.
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 2

During the late 1990s, DSS grew rapidly as small school
districts faced more complex challenges and
pressures to cut costs, particularly in administration. In
response to this growth, DSS organized itself
into four practice departments—Procurement and Systems,
Information Technology, Contract
Negotiation, and Facilities Planning—to deal with different
types of engagements. Business came
primarily through contacts the five founders had developed.
Once DSS was engaged, the project
would be referred to the head of the appropriate practice group
who would assign consultants to the
project.
By 2005, a number of changes had begun to affect DSS. First,
the founders were cutting back their
involvement in the company. As a result, management decisions
were being passed on to new leaders,
including people hired from other consulting companies. In
addition, since much of DSS’s business
was generated through contacts established by the founders,
their reduced involvement was creating a
need for new marketing strategies. Second, the types of
problems for which districts were looking for
help were becoming more diverse and often didn’t fit clearly
into a specific practice area. The
increasing complexities districts were facing were both reducing
the need for the relatively
straightforward projects DSS had been working on and creating
demands for new types of services.
Finally, state standards for school districts were diverging from
one another, so that certain issues
were more important in one region than in another. All of these
changes led to stagnation in revenue
growth for DSS.

Because of these changes, the founders decided that a shift in
strategy would be necessary for DSS to
continue to grow and be successful. As a first step, they
promoted Meg Cooke to the position of Chief
Operating Officer. Meg had joined DSS in the Contract
Negotiation group about four years earlier
after spending time with a larger east coast firm. Two years
after joining DSS, she had been promoted
to head the Contract Negotiation group. The founders and Meg
had concluded that if DSS was to
continue to be successful, it would need to expand beyond its
traditional customer base of small
districts and offer services to larger districts much more than it
had in the past. They felt that
accomplishing this would require developing new services and
reorganizing into a more cross-
functional, customer-focused organization. A major part of the
strategic change involved reorganizing
DSS from a purely practice-oriented functional structure to a
hybrid structure. Most of the
consultants would now be assigned to new cross-functional
teams that would be responsible for
marketing and delivering services to districts within a particular
geographic region. The practice
groups were maintained to provide specialized expertise to
support the cross-functional teams in their
work but with many fewer staff members than in the past.
The new cross-functional teams were given two responsibilities.
Over the long run, the teams were to
build relationships with the school districts in their regions and
provide a full range of DSS consulting
services to those districts. The teams were also to develop new
consulting offerings in response to
district needs. The expectations were that the cross-functional

teams would eliminate the functional
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 3
“silos” that constrained the services DSS could provide and help
DSS develop services that could be
sold to larger districts. Both these were seen as crucial steps in
the plan to grow DSS.
Chris Peterson and the Southwest Region Team
Chris Peterson joined DSS in 2001. She started her career as a
high school teacher in a small school
district in Iowa. When the district began to deploy personal
computers, she was asked to head up the
implementation in her school. The process went so smoothly
that she was asked to give up classroom
teaching and work full-time for the district in rolling out
technology across all the schools. After five
years in that job she joined DSS as a consultant in the
Information Technology group. She rose to the
position of project manager in the group and had been very
successful in leading consulting projects.
When the decision was made to reorganize into cross-functional
teams, Chris was seen as a “natural”
to lead one of the teams and was assigned to head the Southwest
Region team.
Chris looked on her new assignment with a mixture of
excitement and apprehension. Much of the
excitement came from the opportunity to lead a permanent team

rather than coordinate individuals for
short consulting projects. Her apprehension came in large part
because of some uncertainties about
how the new strategy would unfold. Chris was aware that many
people were ambivalent about the
new strategy and uncertain about the necessity of the change
and whether or not it was likely to be
successful. The result of this was that there was a great deal of
anxiety among many consultants
about the future of DSS and their roles in the new structure.
Chris also suspected that the strategy
was still evolving and might change as management got a sense
of how well the new organization
was working.
One of the decisions that Meg had made about the new teams
was that the team leaders ought to have
a great deal of flexibility in inviting people to join their teams.
Chris welcomed this opportunity. In
thinking about who she wanted for the team, she considered two
factors. First, she wanted people
who had good skills and were experienced in the DSS
consulting process. Second, she felt she
needed people who would be able to work together well. She
believed this would be important
because of both the nature of the work to be done and her fear
that the anxiety created by the change
would boil over into dissatisfaction if people had trouble
working together.
Chris gave a great deal of thought about who to ask to join the
Southwest Region team. She decided
that one thing that would help the group work together smoothly
would be to select people who
already had some experience in working with one another.
Overall, Chris was quite happy with the

team she was able to put together. She ended up asking two
consultants each from Contract
Negotiations, Procurement and Systems, and Information
Technology, and one consultant from the
Facilities group to join the team, all of whom accepted. Even
though the consultants had not worked
on specific projects with each other in the past, they knew one
another and had a great deal in
common. Nearly all of them had worked on DSS’s annual
Habitat for Humanity project and all had
started at DSS at about the same time. Many members of the
group socialized with one another
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 4
outside of work. At the first group meeting Chris realized that
her strategy had worked well. Two of
the consultants marveled about how nice it would be to work
with people who were both very
competent and friends as well. Another consultant mentioned
that he didn’t know many people at
DSS other than the members of his new team and he was really
looking forward to the project. Like
most DSS consultants, members of Chris’s new team had some
questions about the new strategy and
leadership; however all believed that their new team had
tremendous potential.
Beginning the Work
As DSS was making the transition to the new structure,

consultants continued to finish existing
projects even as they began working with their new teams.
Chris believed it was very important that
her team members be located together as soon as possible even
though the team would not be
working together full-time right away. She believed that co-
locating the team would allow the group
to get a quick start on the major deliverable of developing new
products for DSS and prevent the
group from getting distracted by some of the uncertainties
created by the new structure. Chris was
able to identify some space and a plan that could bring the full
team together. Since none of the other
new team managers felt as strongly about the co-location of
their teams as Chris did, Meg allowed
Chris’s team to move together before the other teams did.
Once the team got settled into its new location, they quickly got
to work. Chris believed that the first
issue for the team would be to share their experiences and use
their collective knowledge to identify
one or more potential new products, and that her initial job
would be to help the group pull together
their experiences. The group had a number of meetings over the
next month discussing their
perspectives. Chris was very pleased with what happened in the
meetings. The team members
seemed comfortable sharing information with one another. If a
disagreement emerged, the team dealt
with it without creating animosity or substantial delay. Chris
was particularly pleased when two of
the team members told her that this was one of the best groups
they had ever been a part of.
Even though they were from different functional areas, the team
members found that they had very

similar experiences in dealing with districts. All of them had at
least one story about how they had
been delayed in a project because the people they were working
with in the district were not able to
get accurate data about budgets or long term plans. What
emerged from the discussions was that
small districts seemed to lack any integrated system for linking
plans and budgets over time. The
superintendent of the district seemed to be the only person who
knew everything that was going on
and if he or she was not available it was difficult to get timely
information. The team concluded that
what small districts needed was an integrated system for
planning and budgeting. Although most
large districts had the systems or the human resources to do
this, the costs were prohibitive for a small
district. The team determined, therefore, that a scaled down
system could provide the level of
planning small districts needed at a price they could afford.
Further, this project both excited the
team and was something they felt they could do well.
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 5
Planning the New Product
As members of the team began finishing the consulting projects
they had been working on, they were
able to devote more time to developing specifications for the
new system. The majority of the team
were now spending nearly all their time working with one

another and saw less and less of the other
consultants who were not on the team. Occasionally people
would bring up what other consultants
had said their teams were doing, but this seldom generated
much interest and was sometimes seen as
almost a distraction to the group. At this point in time, Chris
had two primary goals for the team.
First, she wanted to keep the group focused on the jobs of
defining the new system and determining
exactly how DSS consultants would use it. Second, she wanted
to help the group avoid distractions
and continue to build cohesion.
In addition to working with the team, Chris tried to deal with
people outside the group. She had
developed friendships with two superintendents in small
districts and when she saw them, she took
the opportunity to describe the system her team was developing.
Generally, the feedback she
received was positive and she relayed this to her team. Chris
also met occasionally with Meg to
update her on the project; however these meetings were
generally short. Chris observed that some of
the other team leaders spent more time meeting with Meg than
she did, but she didn’t see that there
was much need for her to do so, given the progress her team was
making.
Developing the Planning and Budgeting System
Once the specific design of the proposed budget and planning
system was complete, Chris felt it was
time to share the work of the team with others. She took a
detailed description of the program out to
a number of districts she had worked with in the past and asked
for comments. She also emailed the

program description to Meg and some of the DSS functional
specialists who would have to provide
some technical support in developing the consulting protocols
and specifying parts of the code for
managing the data base.
The conversations with people in the districts were informative
and more-or-less positive. While
generally expressing support for the new system, people in the
districts raised some specific
questions. Many of the comments or questions were about how
the system would deal with issues
that were unique to a district. A few questions emerged about
the price of the product and how it
would differ from other products already on the market. When
Chris took these comments back to
the group they tried to modify the initial design and
specifications of the program to meet the
concerns that were raised. This worked well in the short run,
but as more comments came in, the
group began to flounder as the team tried to adapt the design to
meet many of the questions from
outsiders.
The reactions from others inside DSS were different from those
in the districts. Most of the
functional specialists who received descriptions of the project
simply acknowledged receiving them
but did not offer any real comments. Meg responded by asking
a couple of questions and saying that
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell

September 10, 2010 6
she and Chris would talk more about it later. Overall, the group
was pleased with these responses; no
one had raised any objections to the program design or
identified any difficulties that would slow the
project down.
As the group worked to change the project specifications in
response to the comments coming in from
the districts, Chris felt that the effective process the group had
developed was beginning to break
down. There were disagreements about how important various
comments actually were and progress
in finalizing the specifications seemed to slow. Team members
began to voice more concerns than
they had in the past about the direction DSS was going and
question whether the team would be able
to accomplish its task. Chris decided that something needed to
be done to get the group back on
track. She cancelled work on the next Friday and had the whole
team meet at a nearby nature
preserve. After a hike, the group returned to Chris’s house for a
barbeque lunch. Following lunch,
the members spent the rest of the afternoon discussing how they
were performing and what they
needed to do to finish designing the project. Overall, this
seemed to work quite well. When the team
got back to work on Monday, they quickly finalized the
specifications and identified the steps that
would be necessary to actually develop the product and
consulting protocols.
The team turned its attention to completing the project. The
project had four components: a database
program provided by a third-party vendor; a program for putting

information into the database
program written by an outside consulting firm; a set of forms
districts would use to organize
information about schedules and budgets; and a set of
instructions for consultants to use in helping
districts use the program and its results. The team split into
sub-groups to work on pieces of the final
project.
Putting together the forms and developing instructions for
consultants were the most challenging
parts of the project. Both of these tasks required detailed
knowledge about the different types of
projects districts might undertake. Although members of the
team had the knowledge and experience
to complete most of this work, they often found that they
needed to draw on the specialized
knowledge of the DSS specialists in the practice groups. When
a specific question came up that the
team could not answer, one member of the Southwest team
would either email a question or have a
face-to-face meeting with the specialist. This worked well for
simple issues but not for more
complex problems. When team members tried to get functional
specialists to spend time working on
these more complex problems, they were often not given much
help and were occasionally rebuffed.
Chris found that she often had to go directly to the manager of
the practice area to try to get support.
Even this didn’t always work. One event typified the problem
Chris was experiencing. She met with
the head of Contract Negotiation to identify the specific
information about a district’s employees that
would need to be entered into the program. He told Chris that
he would ask one of his specialists to
work on it with the team. When one member of Chris’s team

contacted the specialist, he was told that
this project had not been built into her schedule and that she
would not be able to help him until other
things got done.
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 7
When Chris learned of this she scheduled a meeting with Meg to
discuss the difficulty her team was
having in getting support. From Chris’s perspective, the
meeting with Meg did not go particularly
well. Meg seemed sympathetic to the difficulty Chris was
having getting support and suggested that
she could keep working with the practice group managers to get
the final elements of the project
completed. Chris had hoped that Meg would take more direct
action. When Chris reported back to
the team, the overall reaction by team members was negative.
There were a number of comments
about how decisions at DSS seemed to be more “political” under
the new organization and how the
“new Meg” seemed to be playing favorites.
Finishing the Project
Despite the difficulty in getting support from others in the
organization, Chris knew that the project
was close to completion and could still be a success in the
market. Chris conveyed this to her team.
She reminded them that even if they were not getting the type of

support they would like, they had the
experience necessary to finish the program on their own.
Chris’s optimism was contagious. The
team increased their efforts and did independent research to fill
in their own knowledge gaps. The
project came together quickly and within 10 days the team had a
full product ready for beta testing.
A few weeks earlier, Chris had recruited a district that would be
willing to serve as a test site and a
date was scheduled for the team to go into the district to
demonstrate the product.
The Meeting with Meg Cooke
As Chris came into work on Friday morning, she thought back
over the last few months and was quite
pleased. The group had done a terrific job of specifying and
developing a new product that was ready
for a beta test. Initially her team members had doubts about the
new strategy and their new roles but
they had overcome those, and some real obstacles, to finish the
assignment. Chris was looking
forward to sharing this with Meg.
From Chris’s perspective, the Friday morning meeting with Meg
started off very well. Chris outlined
the progress her team had made on the integrated budget and
planning system. She spoke about how
she was managing the beta test for the program and of the
positive comments she was getting from
the district. She also talked about how effective her team was.
They worked together very well, were
cohesive, and made decisions easily and quickly. Chris also
mentioned that a number of the team
members had not supported the reorganization at first but
despite that had invested a great deal of

effort in making the team and project work and were now
committed to the new direction for DSS. In
particular, Chris complimented the team members on their
initiative in finishing the project even
when they didn’t have a great deal of help from the specialists
in the practice groups.
Meg thanked Chris for all the hard work on the project and
mentioned that she had heard very
positive things about Chris’s leadership from members of the
Southwest Region team. Meg then
shifted the conversation and asked Chris for a report about the
types of services districts in her region
might be looking for DSS to provide in the future and whether
some of the other projects the DSS
CHRIS PETERSON AT DSS CONSULTING
Deborah Ancona and David Caldwell
September 10, 2010 8
regional teams were working on would be of interest to the
districts. Chris responded that she had a
general idea of what the other teams had been working on but
did not feel she had sufficient
information to present them to districts at this time. She went
on to say that her team had focused on
their project and that the plan was for them to go out and meet
with all districts in the region after the
project was in a beta test so that they would have something
specific to discuss. She reassured Meg
that although she did not have a clear answer to the question
right now, she would in the near future.
Meg then asked Chris how she saw the integrated budget and

planning system being marketed to
large school districts given that most of them already seemed to
have either systems or personnel to
do this. Chris responded that she understood the concern and
that, at this point in time, large districts
might not be interested in the system in its current form. She
went to say that as the system was
modified and expanded it would very likely be of interest to
larger districts. After this, Chris and
Meg exchanged a few pleasantries and the meeting ended.
The Monday Morning Meeting
When Chris arrived for work on Monday morning she found that
she had a message from Meg asking
if they could meet for coffee at 10:30. Chris was curious about
the meeting, but quickly responded
that she would be available, and the two agreed to meet at a
nearby coffee shop. After getting coffee
and talking a bit about the weekend, Meg told Chris that after
reviewing her team’s project and its
potential, she had decided that DSS would not go forward with
the scheduling and budgeting project.
When Chris asked for the reasons for this decision, Meg replied
that the number of new products DSS
could support was limited and that teams in the other regions
had not reported any interest on the part
of the districts they had worked with for this type of product.
Meg also said that she was concerned
that the project would not be of interest to the large districts.
Chris responded that she certainly
understood the issue about large districts but did not agree with
Meg’s observation. She went on to
say that she did not understand how other regional teams could
say that there would not be a demand
for the product when they did not even know what the planning

and scheduling system could do.
Meg said that she appreciated Chris’s concerns but that the
decision to cancel the project was final.
An awkward silence followed this last exchange. After a
moment or two, Meg said that there was
one more thing left to discuss. She said that the Southwest
Region Team would focus exclusively on
marketing DSS products and not be involved in product
development work in the future and that there
would be some change to the composition of the team. Meg
ended by asking Chris if she was
prepared to lead the group in a new direction or if she would be
more comfortable and successful
returning to the IT practice group as a functional specialist.