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Page 6 of 11 Marchand-Adam et al. Rare Dis Orphan Drugs J 2023;2:3 https://dx.doi.org/10.20517/rdodj.2022.24

hypothesis is uterine origin with migration via the lymphatic pathways. The mechanisms involved in the
pathophysiology of LAM are misunderstood. In particular, they encompass lymphangiogenesis, which is
notably associated with the overexpression of lymphatic growth factors, vascular endothelial growth factor
[51]
(VEGF)-C and VEGF-D, and their receptor VEGF R3, a marker of lymphatic endothelial cells . The level
of blood VEGF-D, which is significantly increased in LAM, is currently the only serum biomarker for LAM
diagnosis. Indeed, high levels of serum VEGF-D (> 800 pg/ml) are specifically observed in LAM, among
pulmonary cystic pathologies. The pathophysiology of LAM also includes a genetic component. Mutations
during tuberous sclerosis concern two tumor suppressor genes: tuberous sclerosis complex 1 (TSC1) and 2
(TSC2), coding respectively for hamartin and tuberin . The TSC1/TSC2 complex allows the inhibition of
[52]
the intracellular signaling pathway involved in cell growth and proliferation, the mTOR-S6k1 [mammalian
[53]
target of rapamycin (mTOR)-S6 kinase 1] pathway . In the case of sporadic LAM, these mutations are
sometimes found at the somatic level and de novo. They are found in lung and kidney lesions, the most
common mutation being that affecting the TSC2 gene. Mutations in these genes lead to a loss of inhibitory
function of the hamartin-tuberin complex and are responsible for the constitutive activation of the mTOR
pathway and subsequent abnormal cell proliferation and growth as well as lung remodeling [Figure 3] .
[54]
Contrariwise, the constitutive activation of Raptor-containing mTORC1 leads to downregulation of
apoptosis and cell survival .
[55]

Current therapy
Recently, purine and pyrimidine nucleotide analogues and immune checkpoint inhibitors were advocated as
potential therapeutic avenues to induce LAM cell death (see for review: ). Likewise, preliminary surveys of
[55]
statins and a cyclo-oxygenase-2 inhibitor of the coxib family (celecoxib) were reported, but supplemental
studies with larger LAM cohorts are needed to validate clinical effectiveness. Also, progesterone as well as
pharmacological inhibitors (oestrogen receptor modulators, gonadotropin-releasing hormone agonists,
aromatase inhibitors) were attempted as potential treatments for LAM but gave unreliable and
unconvincing results . Conversely, several clinical studies have pointed to a beneficial effect of mTOR
[55]
inhibitors, especially rapamycin, on LAM [Figure 3]. Rapamycin (a.k.a., Sirolimus), a macrolide compound
naturally produced by the bacterium Streptomyces hygroscopicus, is currently the reference treatment for this
[56]
pathology . Nevertheless, its effect, which remains only suspensive, is associated with many side effects,
notably an increased risk of infection following the immunosuppression induced by treatment with
[57]
Sirolimus . Also, Sirolimus can be responsible for hematological disorders with a very frequent probability
[56]
of pancytopenia associated with the risks of an infectious event . Although rapamycin favors stabilization
of lung function and improves quality of life, the cessation of rapamycin treatment results in recurrence of
the disease progression, highlighting the imperative need to identify novel targets and contemporary LAM
treatments (see for review: ).
[58]

CATHEPSIN K: A NEW LAM BIOMARKER?
An early immunohistochemical study reported a strong CatK immunoreactivity, which was specifically
restricted to lymphangioleiomyomatosis specimen, compared to other lung samples from angiomyolipomas
and diverse lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema)
used as controls . The specificity of CatK as a putative LAM marker seemed appropriate, according to
[59]
other pulmonary α-SMA-expressing cells that are immuno-negative for CatK or exhibit only a discrete CatK
immunoreactivity, such as myofibroblasts in fibroblast foci of usual interstitial pneumonia . Moreover,
[59]
these α-SMA-expressing cells do not represent diagnostic problems because of their distinctive
morphologies and immunophenotypes. Following this study, authors proposed that CatK could be a useful
additional biomarker for diagnosis in some ambiguous cases. Moreover, they suggested for the first time
that CatK can contribute to the progressive remodelling of lung parenchyma observed in LAM. In an
outstanding study, it was hypothesized that LAM nodule-derived proteases cause cyst formation and tissue