Implicatii ale stresului in evolutia

bolii neoplazice
PROF. DR. CORNELIA NITIPIR
SUU ELIAS
 Cancerul metastatic rezistent la terapia oncologica -> principala cauza
de deces prin cancer
 Procesul de metastazare consta in o serie de etape succesive pe care
celula tumorala trebuie sa le parcurga.
 Tratamentul cancerului metastatic trebuie nu numai sa vizeze celulele
neoplazice, ci si diferiti factori care contribuie la cresterea,
supravietuirea si migrarea acestora.
 Studii clinice si epidemiologice din ultimii ani au identificat diferiti
factori psihosociali precum stresul, depresia cronica, lipsa suportului
social ca factori de risc pentru progresia cancerului. In timp ce dovezile
privind rolul acestora in initierea carcinogenezei sunt contradictorii,
exista dovezi puternice in ceea ce priveste legatura dintre stres,
depresie, izolarea sociala si progresia bolii neoplazice.
Effects of stress on cancer metastasis
The process of cancer metastasis consists of sequential selective steps.
The outcome of each step is influenced by the interaction of metastatic
cells with homeostatic factors. Failure of a tumor cell to complete any
step effectively terminates the process. Therefore, the formation of
clinically relevant metastases represents the survival and growth of
unique subpopulations of cells that pre-exist in primary tumors.

Thaker PH, Sood AK. Neuroendocrine influences on cancer biology. Semin Cancer Biol. 2007;18(3):164-70.
 Main steps in the formation of a metastasis

(A) Cellular transformation and tumor growth. (B) Extensive vascularization must occur if a tumor mass exceeds 1–2
mm in diameter. The synthesis and secretion of angiogenic factors establish a capillary network from the surrounding
host tissue. (C) Migration and invasion of the host stroma by some tumor cells occurs by several parallel mechanisms.
Lymphatic channels offer very little resistance to penetration by tumor cells and provide the most common route for
tumor cell entry into the circulation. (D) Next, detachment and embolization of single tumor cells or aggregates occurs;
most circulating tumor cells are rapidly destroyed. (E) After cancer cells have survived the circulation, they become
trapped in the capillary beds of distant organs by adhering either to capillary endothelial cells or to the subendothelial
basement membrane. (F) Extravasation then occurs, probably by mechanisms similar to those that operate during
invasion. (G) Proliferation within the organ parenchyma completes the metastatic process. To continue growing, the
micrometastasis must develop a vascular network and evade destruction by host defenses. The cells can then invade
blood vessels, enter the circulation and produce additional metastases.
Mediatori neuroendocrini

Efectele catecolaminelor sunt mediate prin receptorii adrenergici

(ADRs): Alpha 1, alpha 2 (ADRA1, ADRA2), b1, b2, b3 (ADRB1,2,3). ADRs
sunt receptori cuplati cu proteinele G.
Proteinele G constituie cea mai mare familie de receptori celulari de
suprafata; Gs – responsabile de stimularea adenilat ciclazei(AC) si
cresterea AMPc, Gi – responsabile de inhibarea AC  SEMNALE
INTRACELULARE RASPUNS CELULAR.
 Raspunsul celular la stimularea unui receptor cuplat cu proteina G
poate sa varieze in diferite celule.
 Au fost raportate concentratii crescute ale catecolaminelor la nivelul
tesutului tumoral ovarian ca raspuns la stres.
Mediatori neuroendocrini
 ADRAs sunt de asemenea exprimate in diferite tipuri de celule
canceroase (ex: cancer de colo, prostata)
 Doxazosin – antagonist selectiv al ADRA1, utilizat in tratamentul HTA,
in vitro s-a demonstrate ca inhiba proliferarea celulelor canceroase
prostatice.
ADRBs – identificati la nivelul mai multor tipuri de celule canceroase,
inclusiv mamare si ovariene.
 ADRB1,2,3 – sunt cuplate cu proteine Gs  ↑AC si ↑AMPc
 ADRB2 – cuplate si cu proteinele Gi
 Norepinephrine-, dopamine- and glucocorticoid-mediated signaling pathways in
tumor, endothelial and endothelial progenitor cells

(A) In ovarian cancer cells, NE acting through ADRBs induces synthesis and release of the
proangiogenic cytokines IL-6, IL-8 and VEGF. NE also induces synthesis of MMPs and
stimulates migration and invasion of ovarian, colon and head and neck cancer cells; in
breast, cervical and lung cancer cells, GCs acting through the GC receptor inhibit
chemotherapy-induced apoptosis and promote cancer cell survival. GC: Glucocorticoid;
GCR: Glucocorticoid receptor; MMP: Matrix metalloproteinase; NE: Norepinephrine

Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol. 2010;6(12):1863-81.
(B) DA acting through DR2 receptors in tumor endothelial cells inhibits proliferation
of these cells by inhibiting phosphorylation of VEGFR-2, MAPK and FAK. (C) DA
decreases ERK1/ERK2-mediated MMP-9 synthesis and release by endothelial
progenitor cells and thereby inhibits their mobilization from the bone marrow. Thus,
DA prevents the participation of EPCs in tumor neovascularization.DA: Dopamine;
EC: Endothelial cell; EPC: Endothelial progenitor cell; FAK: Focal adhesion kinase;
MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase;
Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol. 2010;6(12):1863-81.
Stresul si angiogeneza
 Angiogeneza este un proces complex, esential pentru cresterea
tumorala si metastazare. Procesul de neovascularizatie implica
eliberarea factorilor proangiogenici de catre celulele tumorale (VEGF, IL-
6, TGF-α and -β and TNF-α). Angiogeneza poate fi stimulata si de
dezechilibrul dintre factorii pro si antiangiogenici.
 Noradrenalina – s-a observat in vitro ca determina cresterea expresiei
VEGF la nivelul celulelor tumorale ovariene si la nivelul tesutului adipos
prin calea ADRB-cAMP, efect ce a fost inhibat prin administrarea de
propranolol (b blocant).
 IL6 – factor proangiogenic; nivel crescut in vitro la nivelul tumorilor
ovariene, dupa injectarea NA.
Stresul si angiogeneza
 In vivo: stresul cronic indus de perioadele zilnice de imobilizare la
soricei cu neoplasm ovarian a determinat niveluri crescute de
catecolamine si accelerarea cresterii masei tumorale. Densitate capilara
intratumorala, expresia VEGF, MMP2 si MMP 9 - mai mari la soriceii
stresati. Administrarea b blocantelor (propranolol) a incetinit progresia
tumorala.
Adeziunea celulara
 Adeziunea celulelor tumorale la matricea extracelulara influenteaza
capacitatea lor de a invada alte tesuturi si de a metastaza. Matricea
extracelulara este formata din colagen de tip I si IV, proteoglicani,
laminine, fibronectina si alte glicoproteine.
 Adeziunea celulelor la aceste proteine este mediata de integrine
( protein transmembranare heterodimerice)
 Stimularea ADRB2 - AMPc – stimuleaza adeziunea celulara prin
intermediul integrinelor
Migrarea si invazia celulelor tumorale
 O etapa importanta -> capacitatea celulelor tumorale de a depasi
membrana bazala si de a ajunge in circuitul sangvin.
 Catecolaminele – stimuleaza productia de metaloproteinaze (MMP)
de catre celulele tumorale si de catre macrofagele peritumorale.
 Autorii au evaluat efectele catecolaminelor si ale cortizonului asupra
invazivitatii celulelor ovariene (capacitatea de a penetra matricea
extracelulara).
NA a crescut invazivitatea cu > 89%; Adrenalina – 64%-76%; cortizolul
nu a afectat invazivitatea tumorala.
Betablocantele au scazut invazivitatea determinata de catecolamine.
NA a crescut productia MMP-2 si MMP-9.

Studii efectuate si pe alte linii celulare (celule tumorale colonice sau din
sfera ORL) au obtinut aceleasi rezultate.
Effect of chronic stress on
breast cancer growth in mice
that were injected with
breast cancer cells. (A)
Schematic illustrating in vivo
animal models. (B)
Quantification of tumor
weight, tumor volume and E
(epinephrine) concentration
in plasma in control mice and
in chronic stress mice. (C)
CD206 (marker for Mϕ)
expression in tumor dissected
from control mice and
chronic stress mice.
Apoptoza
 Studii in vitro – adrenalina a inhibat apoptoza celulelor tumorale
mamare si prostatice, prin ADRB2, care a dus la fosforilarea intracelulara
a Bcl-2 (o proteina proapoptotica), devenind inactiva. Bcl-2 nefosforilata
are rol in initierea apoptozei.
 GC:
• au si ei rol in inhibarea apoptozei
• cresc expresia genelor antiapoptotice
• unele studii sugereaza faptul ca GC cresc rezistenta la efectele chimioterapiei
( tumorile solide)
• Insa, induc apoptoza in leucemia limfoblastica
Materiale si metode:
• linii celulare – adenocarcinom ductal pancreatic cu mutatii in genele
p53 si KRAS prezente (mutatii driver) injectate la soricei; liniile celulare –
supraexprima luciferaza ( enzima care oxideaza luciferina in organismele
vii (Luciferină + O2 → Oxiluciferină + lumina)
• progresia tumorala obiectivata – prin imagistica optica pentru
bioluminiscenta
• factorul stresor - imobilizare
• 4 grupuri : control + placebo; control + b blocant; stress + placebo;
stress + b blocant
 Beta-blockade reversed stress-enhanced
pancreatic cancer progression
A. Tumor progression was tracked using
non-invasive bioluminescence
imaging in mice that were exposed
to control (black) vs. stress
conditions (red) and treated with
propranolol (dotted line) or placebo
(solid line)
B. Representative images of mice taken
on day 42 after tumor cell injection.
Mice were exposed to control vs.
stress conditions and treated with
propranolol vs. placebo. Black tape
in each panel covered
autoluminescent osmotic minipumps
used for drug delivery. Luminescence
scale: p/sec/cm2/sr.
C. Primary tumor mass was determined
on day 42 after tumor cell injection.
D. The magnitude of tumor cell invasion
into pancreas adjacent to the
primary tumor was quantified by ex
vivo bioluminescence imaging after
surgical resection of the primary
tumor. Luciferase activity: ×106 p/sec.

Beta-blockade slows pancreatic cancer progression

Alti mediatori implicati
DOPAMINA • Receptori DR2 • Inhiba angiogeneza si
• Stresul acut – nivel DA cresterea tumorala prin
↑ ↓VEGF
• Stresul chronic – nivel • Inhiba proliferarea LT
DA ↓ citotoxice.
• Stimuleaza calea HIF1a
ce conduce la proliferare
tumorala.

PROLACTINA • Celule tumorale mamare • Stimuleaza cresterea

pot prezenta receptori tumorala mamara
pentru prolactina • Studii epidemiologice 
niveluri crescute ale
prolactinei la persoanele
cu factori de risc pentru
neoplasmul mamar (ex:
nuliparitatea, menarha
precoce)
Alti mediatori implicati
OXITOCINA • Predominant efect • Studii  Inhiba cresterea
anxiolitic tumorala in cancerul mamar,
• Receptori pentru endometrial, al SNC
oxitocina au fost • Studii  Stimuleaza cresterea
identificati la neoplasmului pulmonar,
nivelul celulelor sarcomului Kaposi
canceroase • Promoveaza migrarea, invazia
mamare, ovariene si metastazarea celulelor
si prostatice. tumorale prin calea de
semnalizare Arrestin2-
dependent ERK-VEGF/MMP-2

SUBSTANTA P • Receptor • Stimuleaza cresterea

neurokinin 1 tumorala in cancerele: de san,
colonice, pulmonare
• Stimuleaza mitoza celulara
Alte studii recente …
 ADRBs si cancerul de prostata
Supraexpresie ADRB2 la nivelul celulelor
tumorale prostatice metastazate.
Catecolaminele activeaza ADRB2  ↑cAMP
 ↑ PKA (protein kinaza A)
1. activeaza factori de crestere tumorala
(CREB - cAMP responsive element
binding protein)
2. CREB – induce diferentierea
neuroendocrina si angiogeneza
3. inhiba factori antiproliferativi
4. fosforileaza si inhiba promoterul mortii
celulare asociat BCL-2 (BAD), inducand
rezistenta celulelor tumorale prostatice
la apoptoza.
5. activeaza calea de semnalizare PI3K-AKT
 stimuleaza VEGF si angiogeneza
Zhao Y, Li W. Beta-adrenergic signaling on neuroendocrine differentiation, angiogenesis, and metastasis in prostate cancer progression. Asian J
Androl. 2019;21(3):253–259. doi:10.4103/aja.aja_32_18
 B blocantii si
cancerul de
prostata
DOVEZI
 Studiu prospectiv
 Nu a influentat incidenta,
mortalitatea generala.
 In subgrupul pacientilor
tratati cu ADT s-a observat o
scadere de pana la 5 ori a
mortalitatii.
Posibila explicatie: ADRB2s
activeaza receptorii
androgenici si poate sa
scada eficienta ADT.
 Stresul cronic influenteaza factorii legati
de imunitate si inflamatie
Stresul chronic si hormonii de stres stimuleaza eliberarea citokinelor pro
inflamatorii determinand carcinogeneza si metastazarea.
Creste IL6, TNF alpha, IL10 – citokine pot acționa în toate etapele
dezvoltării tumorale, inclusiv inițierea, promovarea, transformarea
malignă, invazia și metastazarea prin mutații, modificare epigenetică și
reglare a micromediului tumoral.
Hormonii de stress scad activitatea celulelor prezentatoare de antigen
(monocite, macrophage, cel dendritice, cel NK) ce duce la scaderea IL 12
si INF gamma.
Stresul chronic – activeaza calea de semnalizare COX-2/PGE2 ce
actioneaza la nivelul micromediului tumoral inhiband raspunsul imun
asupra celulei tumorale si stimuland neoangiogeneza tumorala
(+VEGF).
 Effects of stress hormones on the
immune system. Stress hormones
stimulate pro-tumorigenic immune
cells to produce IL-6, IL-10, and
other cytokines, and activate the
COX-2/PGE2 pathway to produce
VEGF, which together affect the
tumor microenvironment to
suppress tumor immunity. The
decrease in IL-12 and the increase
in IL-10 lead to selective Th1
inhibition, thereby suppressing the
CTL-mediated cellular immunity
and interferon production.

Dai S, Mo Y, Wang Y, Xiang B, Liao Q, Zhou M, Li X, Li Y, Xiong W, Li G, Guo C, Zeng Z. Chronic Stress Promotes Cancer Development.
Front Oncol. 2020 Aug 19;10:1492. doi: 10.3389/fonc.2020