A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer.
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ immunology
Cancer-Associated Fibroblasts
/ immunology
Carcinoma, Ductal, Breast
/ immunology
Carcinoma, Lobular
/ immunology
Case-Control Studies
Combined Modality Therapy
Female
Follow-Up Studies
Humans
Lymphocytes, Tumor-Infiltrating
/ immunology
Middle Aged
Neoplasm Recurrence, Local
/ immunology
Prognosis
Receptor, ErbB-2
/ metabolism
Receptors, Estrogen
/ metabolism
Receptors, Progesterone
/ metabolism
Survival Rate
Tumor Microenvironment
/ immunology
CDH11
Cadherin 11
Cancer-associated fibroblasts
Luminal breast cancer
Metastases
Stroma
TILs
Tumor infiltrating lymphocytes
Tumor micro-environment
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
14 07 2020
14 07 2020
Historique:
received:
03
01
2020
accepted:
30
06
2020
entrez:
16
7
2020
pubmed:
16
7
2020
medline:
6
11
2020
Statut:
epublish
Résumé
Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4 This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.
Sections du résumé
BACKGROUND
Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients.
METHODS
Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF).
RESULTS
We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4
CONCLUSIONS
This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.
Identifiants
pubmed: 32665033
doi: 10.1186/s13058-020-01311-9
pii: 10.1186/s13058-020-01311-9
pmc: PMC7362513
doi:
Substances chimiques
Biomarkers, Tumor
0
Receptors, Estrogen
0
Receptors, Progesterone
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
76Subventions
Organisme : Institut National du Cancer
ID : 9963
Pays : International
Organisme : Ligue Nationale Contre le Cancer
ID : Labelisation
Pays : International
Organisme : Institut Curie
ID : PIC
Pays : International
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