Rak z komórek merkla – Patofizjologia i mechanizm

Rak z komórek merkla
Patofizjologia i mechanizm

Rak z komórek Merkla (MCC) jest rzadkim, agresywnym nowotworem neuroendokrynnym skóry, rozwijającym się na drodze dwóch głównych mechanizmów patogenetycznych: integracji wirusa Merkel cell polyomavirus (MCPyV) w genom gospodarza oraz uszkodzeń DNA indukowanych promieniowaniem UV. MCPyV odpowiada za 60-80% przypadków MCC, gdzie transformacja nowotworowa wymaga integracji genomu wirusa oraz skrócenia dużego antygenu T, co umożliwia ekspresję onkoprotein wirusowych LT i ST. Antygeny te inaktywują supresory nowotworowe RB1 i p53 oraz aktywują szlak PI3K/AKT/mTOR, promując proliferację i przeżycie komórek nowotworowych. MCC MCPyV-pozytywne charakteryzuje się niskim obciążeniem mutacyjnym (mediana 12,5 mutacji na eksom), natomiast MCPyV-negatywne wykazują wysokie obciążenie mutacyjne (mediana 1121 mutacji), z wyraźnym „podpisem UV” i mutacjami w genach RB1, TP53 oraz szlakach PI3K-AKT-mTOR i NOTCH. Immunosupresja oraz starzenie układu odpornościowego zwiększają ryzyko rozwoju MCC, co podkreśla rolę układu immunologicznego w kontroli tego nowotworu.

Patogeneza raka z komórek Merkla

Rola wirusa polyoma komórek Merkla
Indukcja przez promieniowanie UV
Rola immunosupresji

Wspólne programy onkogenne w obu typach raka z komórek Merkla

Kluczowe szlaki sygnałowe w MCC
Mikrootoczenie guza i inwazja naczyniowa

Aberracje genetyczne i chromosomowe
Implikacje kliniczne i terapeutyczne
Podsumowanie

Kolejne rozdziały

Patogeneza raka z komórek Merkla

Rak z komórek Merkla (ang. Merkel cell carcinoma, MCC) jest rzadkim, ale wysoce agresywnym nowotworem neuroendokrynnym skóry. Jego patogeneza jest złożona i może przebiegać według dwóch odrębnych mechanizmów, które pomimo różnej etiologii prowadzą do podobnych obrazów klinicznych i prognozy.¹²

Rola wirusa polyoma komórek Merkla

W 2008 roku dokonano przełomowego odkrycia – zidentyfikowano wirusa polyoma komórek Merkla (Merkel cell polyomavirus, MCPyV), który obecnie uznawany jest za główny czynnik etiologiczny tego nowotworu. Wirus ten odpowiada za około 60-80% wszystkich przypadków MCC.¹³⁴

Transformacja nowotworowa indukowana przez MCPyV wymaga wystąpienia dwóch kluczowych zdarzeń molekularnych:⁵⁶

Integracja genomu wirusowego do genomu gospodarza
Skrócenie (truncation) dużego antygenu T, co uniemożliwia replikację wirusa, ale pozwala na dalszą ekspresję onkoprotein wirusowych

Niska prawdopodobieństwo jednoczesnego wystąpienia obu tych zdarzeń może tłumaczyć rzadkość występowania MCC, pomimo powszechności infekcji MCPyV w populacji.⁵

Mechanizm onkogenezy indukowanej przez MCPyV

W procesie rozwoju MCC związanego z wirusem, kluczową rolę odgrywają dwa antygeny wirusowe:⁵⁴⁷

Duży antygen T (LT) – w formie skróconej zachowuje domenę wiążącą białko retinoblastoma (RB1), co umożliwia inaktywację tego ważnego supresora nowotworowego. Prowadzi to do uwolnienia czynnika elongacyjnego 2 (EF2) i w konsekwencji do progresji cyklu komórkowego do fazy S, co pozwala komórkom uniknąć kontroli wzrostu.⁶⁷
Mały antygen T (ST) – wykazuje silne działanie onkogenne, które zależy od unikalnej domeny LSD (LT-stabilizing domain). Domena ta hamuje aktywność kilku ligaz E3 ubikwityny i jest niezbędna do aktywności onkogennej ST zarówno in vitro, jak i in vivo. ST promuje miogenezę i proliferację komórek poprzez aktywację szlaku sygnałowego PI3K-AKT-mTOR.⁵⁶

Badania wykazują, że proliferacja i przeżycie komórek MCC pozytywnych pod względem MCPyV zależą od obecności obu antygenów wirusowych T.⁵ Ponadto, nowotwory MCPyV-pozytywne charakteryzują się niskim obciążeniem mutacyjnym, z medianą zaledwie 12,5 mutacji pojedynczych nukleotydów na eksom, oraz niewielkimi oznakami uszkodzeń wywołanych przez promieniowanie UV.⁶²

Indukcja przez promieniowanie UV

Drugim mechanizmem patogenetycznym MCC jest indukcja nowotworowa spowodowana przewlekłą ekspozycją na promieniowanie ultrafioletowe (UV).¹² Nowotwory MCC negatywne pod względem MCPyV (MCPyV-) wykazują charakterystyczny wzorzec licznych mutacji DNA związanych z uszkodzeniem spowodowanym przez promieniowanie UV.⁴

W przeciwieństwie do MCC związanego z wirusem, nowotwory MCPyV-negatywne cechują się:⁶⁶³

Wysokim obciążeniem mutacyjnym (mediana 1121 somatycznych mutacji pojedynczych nukleotydów na eksom)
Wyraźnym „podpisem UV” w mutacjach
Częstymi aberracjami w genach supresorowych nowotworów, takich jak RB1, TP53
Mutacjami w szlaku PI3K-AKT-mTOR oraz szlaku NOTCH
Zaburzeniami w kinazach N-terminalnych x-Jun (JNK) (MAP3K1, TRAF7)

Co interesujące, promieniowanie UV może również odgrywać rolę w karcynogenezie wirusowej poprzez przyczynianie się do lokalnej immunosupresji, co sprzyja replikacji wirusa i jego integracji.²⁸

Rola immunosupresji

Immunosupresja jest istotnym czynnikiem ryzyka rozwoju MCC. Pacjenci z obniżoną odpornością, szczególnie ci z nowotworami hematologicznymi, zakażeniem HIV, chorobami autoimmunologicznymi lub po przeszczepach narządów, są w grupie wysokiego ryzyka.⁹⁴

Istnieją silne dowody na to, że MCC jest ściśle regulowany przez układ odpornościowy, co może tłumaczyć tendencję do występowania tego nowotworu w późniejszym wieku życia. Z wiekiem dochodzi do starzenia się układu odpornościowego (immunosenescencja), co osłabia zdolność organizmu do kontroli infekcji wirusowej i może umożliwiać rozwój MCC.¹⁰

Związek między immunosupresją a zwiększonym ryzykiem MCC, wraz z danymi wskazującymi na lepsze rokowanie w guzach z wysoką infiltracją limfocytów T CD8+, stał się uzasadnieniem dla zastosowania immunoterapii w leczeniu MCC.¹¹¹²

Wspólne programy onkogenne w obu typach raka z komórek Merkla

Pomimo odrębnych dróg patogenetycznych, zarówno MCC związany z wirusem, jak i indukowany przez UV, wykazują podobne cechy kliniczne, rokowanie i odpowiedź na leczenie.¹ To podobieństwo wynika z aktywacji co najmniej trzech wspólnych programów transkrypcyjnych o działaniu onkogennym:¹¹³

Zwiększona proliferacja komórkowa – oba typy MCC charakteryzują się wysokim wskaźnikiem proliferacji z podwyższonym poziomem genów zależnych od cyklu komórkowego, co wynika z inaktywacji supresorów nowotworowych RB i p53
Silna sygnatura MYC – spowodowana aktywacją MYCL przez wirusa lub amplifikacją genową
Osłabiony program różnicowania neuroendokrynnego – napędzany przez czynnik transkrypcyjny ATOH1

W przypadku nowotworów MCPyV-pozytywnych, antygeny wirusowe T inaktywują supresory nowotworowe pRb i p53, podczas gdy w MCC negatywnych pod względem wirusa, podobne szlaki onkogenne są aktywowane przez mutacje indukowane przez UV.¹³

Kluczowe szlaki sygnałowe w MCC

Niezależnie od mechanizmu inicjującego, kluczowymi szlakami sygnałowymi w patogenezie MCC są:¹³³⁶

Szlak PI3K/AKT/mTOR – jest nadaktywny w MCC i odgrywa istotną rolę w proliferacji i przeżyciu komórek nowotworowych. ST wirusa MCPyV aktywuje ten szlak, co promuje translację zależną od czapeczki i proliferację komórek
Szlak MAPK – wspiera proliferację komórek nowotworowych, ich przeżycie i oporność na apoptozę
Szlak p53 – inaktywacja p53 obserwowana jest w obu podtypach MCC, o czym świadczy skuteczność inhibitorów MDM2 ukierunkowanych na szlak p53 u pacjentów z MCC

Badania sekwencjonowania DNA wykazały, że w nowotworach MCPyV-negatywnych często występują mutacje w genach RB1, p53, PIK3CA, AKT1, PIK3CG, HRAS, NF1, FGFR2, BAP1 i EZH2, co potwierdza kluczową rolę tych szlaków w patogenezie MCC.³³

Mikrootoczenie guza i inwazja naczyniowa

Mikrootoczenie guza (tumor microenvironment, TME) odgrywa centralną rolę w progresji choroby i ucieczce spod nadzoru immunologicznego.¹³ Składa się ono z mieszaniny makrofagów związanych z guzem, regulatorowych i cytotoksycznych limfocytów T oraz charakteryzuje się podwyższoną ekspresją cząsteczek punktów kontrolnych układu immunologicznego, takich jak PD-L1, co przyczynia się do tworzenia immunosupresyjnej niszy.¹³¹¹

Badania wskazują, że inwazja naczyniowa jest wczesnym zdarzeniem w patogenezie MCC. W 93% próbek guzów MCC obserwuje się wewnątrznaczyniowe komórki nowotworowe, przy czym inwazja naczyń limfatycznych (lymphovascular invasion, LVI) występuje w 66% przypadków, a inwazja naczyń krwionośnych (blood vascular invasion, BVI) w 3% przypadków. W 24% próbek obserwuje się oba typy inwazji.¹⁴ Wysoka częstość inwazji naczyniowej może wyjaśniać wyjątkowo agresywny przebieg kliniczny MCC i jest obserwowana już w bardzo małych guzach o średnicy 5 mm.¹⁴

Co istotne, w MCC obserwuje się również obecność fibroblastów związanych z nowotworem (cancer-associated fibroblasts, CAFs) wydzielających IL-6, które mogą wpływać na niekorzystne rokowanie poprzez hamowanie migracji limfocytów T CD8+ do guza.¹⁵¹⁵

Aberracje genetyczne i chromosomowe

Aberracje chromosomowe częściej występują w MCC negatywnych pod względem wirusa niż w nowotworach MCPyV-pozytywnych. Ich obecność koreluje z większym rozmiarem guza MCC i zwiększonym ryzykiem przerzutów.⁶

Różnice w obciążeniu mutacyjnym między MCPyV-pozytywnymi i MCPyV-negatywnymi przypadkami MCC są znaczące. Nowotwory MCPyV-negatywne mają wyższy ogólny wskaźnik mutacji, z medianą 1121 somatycznych mutacji pojedynczych nukleotydów w porównaniu do zaledwie 12,5 w nowotworach MCPyV-pozytywnych.⁶

Badania pokazują również, że w około 75% przypadków MCC wykrywa się ekspresję antyapoptotycznego białka bcl-2, co sugeruje, że jest to jeden z mechanizmów pozwalających komórkom nowotworowym uniknąć śmierci komórkowej.¹⁶

Implikacje kliniczne i terapeutyczne

Zrozumienie patogenezy MCC ma istotne implikacje dla diagnostyki, rokowania i leczenia:¹⁷⁷¹²

Badanie obecności MCPyV przy rozpoznaniu MCC jest zalecane, ponieważ może pomóc w przewidywaniu rokowania pacjentów – pacjenci z przeciwciałami przeciwko onkoproteiną MCPyV mają lepsze rokowanie
Wysoka immunogenność MCC przyczyniła się do zatwierdzenia inhibitorów punktów kontrolnych układu immunologicznego (avelumab, pembrolizumab) jako skutecznej opcji terapeutycznej dla chorych z przerzutowym MCC
Wysoki poziom mutacji w nowotworach MCC (TMB) sprawia, że są one bardziej podatne na immunoterapię

W ostatnich latach prowadzone są badania nad wykorzystaniem obecności onkoprotein MCPyV w MCC do opracowania terapii ukierunkowanych dla nowotworów MCPyV-pozytywnych.¹⁸ Ponadto trwają prace nad przezwyciężeniem oporności na inhibitory punktów kontrolnych układu immunologicznego poprzez jednoczesne celowanie w mikrootoczenie guza, np. poprzez hamowanie składników macierzy zewnątrzkomórkowej, metaloproteinaz macierzy lub sygnalizacji integryn.¹³

Ostatnio rozpoczęto badania kliniczne nad nowym preparatem IFx-Hu2.0, który działa jako agonista odporności wrodzonej i ma na celu przezwyciężenie pierwotnej oporności na inhibitory punktów kontrolnych.¹⁹

Podsumowanie

Rak z komórek Merkla rozwija się według dwóch odrębnych mechanizmów patogenetycznych: integracji wirusa Merkel cell polyomavirus (MCPyV) do genomu komórek lub poprzez uszkodzenia DNA wywołane promieniowaniem UV. Niezależnie od etiologii, oba typy nowotworu aktywują podobne szlaki onkogenne, w tym inaktywację supresorów nowotworowych RB i p53, aktywację szlaku PI3K/AKT/mTOR oraz sygnaturę MYC. Zrozumienie złożonej patogenezy MCC przyczyniło się do rozwoju nowych strategii terapeutycznych, w szczególności immunoterapii, która wykorzystuje wysoką immunogenność tego nowotworu.¹²⁰¹³

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Materiały źródłowe

#1 Molecular Pathogenesis of Merkel Cell Carcinoma – PubMed
https://pubmed.ncbi.nlm.nih.gov/33228463/
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with two distinct etiologies. Clonal integration of Merkel cell polyomavirus DNA into the tumor genome with persistent expression of viral T antigens causes at least 60% of all MCC. UV damage leading to highly mutated genomes causes a nonviral form of MCC. Despite these distinct etiologies, both forms of MCC are similar in presentation, prognosis, and response to therapy. At least three oncogenic transcriptional programs feature prominently in both forms of MCC driven by the virus or by mutation. Both forms of MCC have a high proliferative growth rate with increased levels of cell cycle-dependent genes due to inactivation of the tumor suppressors RB and p53, a strong MYC signature due to MYCL activation by the virus or gene amplification, and an attenuated neuroendocrine differentiation program driven by the ATOH1 transcription factor.
#2 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression. […] Given the increased risk of MCC in patients with immune deficiencies or treated with immunosuppressive therapies, the presence of pathogens was assessed through whole-transcriptome sequencing. This study identified a new human polyomavirus, MCPyV, and determined that the viral DNA was clonally integrated into the genome of MCC cells.
#2 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
MCPyV+ MCC tumours also express ST. Although its exact molecular functions are not well understood, MCPyV ST has strong oncogenic activity. […] MCPyV+ MCC cells typically contain very few mutations, copy number variations or evidence of UV damage. By contrast, MCPyV MCCs show a very high frequency of DNA mutations associated with UV damage, which are also typically evident in other skin cancers associated with sun exposure. […] Further support for the two distinct subtypes of MCC has emerged from DNA sequencing studies of MCC samples, which relied on sequencing of cancer-specific genes, whole exomes or whole genomes. These studies observed that MCC samples fell into two categories: one form characterized by numerous mutations reflecting UV damage to the DNA and another that contained integrated MCPyV DNA, few somatic mutations and little evidence of UV damage.
#3
https://link.springer.com/article/10.1007/s13671-018-0221-1
To describe updates on the pathogenesis, diagnosis, and management of Merkel cell carcinoma (MCC). […] Sequencing studies revealed that MCCs have either a low mutational burden and integrated Merkel cell polyomavirus (MCPyV), or they have a high number of ultraviolet-associated somatic mutations and no MCPyV. […] Approximately 80% of MCCs are MCPyV driven, whereas MCPyV-negative tumors have mutations in genes such as p53 and RB1. […] MCC is highly immunogenic, and recently, the anti-PD-L1 antibody avelumab was approved to treat metastatic MCC. […] Defined the mutation spectra of MCPyV-negative and MCPyV-positive MCC tumors. […] Detected tumor harboring mutations of MCPyV-negative tumors in Rb1, p53, PIK3CA, AKT1, PIK3CG, HRAS, NF1 and FGFR2. […] Identified mutations in Rb1, p53, PIK3CA, BAP1, AKT1 and EZH2 in MCPyV-negative MCC tumor samples.
#3
https://link.springer.com/article/10.1007/s13671-018-0221-1
Identified mutations in Rb1, p53, PIK3CA, HRAS, PRUNE2 and NOTCH in MCPyV-negative MCC. […] Activation of the PI3K/AKT pathway in Merkel cell carcinoma. […] Activation of PI3K signaling in Merkel cell carcinoma. […] Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas. […] First randomized clinical trial of immune checkpoint inhibition for treating metastatic MCC. […] Randomized clinical trial that led to avelumab being the first FDA-approved drug for metastatic MCC.
#4 Merkel-cell carcinoma – Wikipedia
https://en.wikipedia.org/wiki/Merkel-cell_carcinoma
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer occurring in about three people per million members of the population. Factors involved in the development of MCC include the Merkel cell polyomavirus (MCPyV or MCV), a weakened immune system, and exposure to ultraviolet radiation. […] Several factors are involved in the pathophysiology of MCC, including MCV, ultraviolet radiation (UV) exposure, and weakened immune function. […] The MCV is a small double-stranded DNA virus that is believed to contribute to the development of the majority of MCC. About 80% of MCC tumors are infected with MCV, with the virus integrated into the host genome in a monoclonal pattern. […] Central to the understanding of the pathogenicity of MCV are two viral proteins expressed in infected cells known as the large tumor antigen (LT) and small tumor antigen (sT.
#4 Merkel-cell carcinoma – Wikipedia
https://en.wikipedia.org/wiki/Merkel-cell_carcinoma
About 20% of MCC tumors are MCV negative. In contrast to MCV-induced MCC, these tumors tend to have much higher mutational burdens with mutational signatures characteristic of UV damage. […] The incidence of MCC is increased in conditions with defective immune functions such as malignancy, HIV infection, and organ transplant patients, etc.
#5 The biology and treatment of Merkel cell carcinoma: current understanding and research priorities | Nature Reviews Clinical Oncology
https://www.nature.com/articles/s41571-018-0103-2
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. […] In most parts of the world, the majority of MCCs are caused by the monoclonal integration of Merkel cell polyomavirus (MCPyV), and the remainder are associated with exposure to ultraviolet light. […] Oncogenic transformation by MCPyV is hypothesized to require two events: integration of the viral genome into the host genome and truncation of LT to render the viral genome incapable of replication. […] The integrated and mutated virome no longer produces MCPyV virions. The very low probability of this required combination of events might explain why MCC is rare despite the apparent ubiquity of MCPyV infection.
#5 The biology and treatment of Merkel cell carcinoma: current understanding and research priorities | Nature Reviews Clinical Oncology
https://www.nature.com/articles/s41571-018-0103-2
In virus-positive MCC (VP-MCC), the cell of origin is infected by wild-type Merkel cell polyomavirus (MCPyV), which undergoes episomal replication. Rarely, MCPyV can become integrated into the host cell genome and further acquires a truncating mutation of the large T antigen (LT), resulting in deficient viral replication with continued production of viral oncoproteins. […] Evidence suggests that cultured VP-MCC cells are dependent upon the presence of both viral T antigens for proliferation and survival. […] The common amino-terminal region of viral T antigens associates with heat shock cognate 71 kDa protein, with roles in the regulation of viral replication and possibly tumour cell proliferation. […] Multiple lines of evidence suggest that ST has a critical role in VP-MCC oncogenesis. ST expression is sufficient to transform rat-1 fibroblasts in culture.
#5 The biology and treatment of Merkel cell carcinoma: current understanding and research priorities | Nature Reviews Clinical Oncology
https://www.nature.com/articles/s41571-018-0103-2
The MCPyV ST has a distinct domain known as the LT-stabilizing domain (LSD), which has been proposed to inhibit the activity of several E3 ubiquitin ligases. […] The LSD domain is required for oncogenic activity by ST in vitro and in vivo, thus supporting a critical role of this domain in the oncogenesis of MCPyV-induced MCC.
#6 Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies
https://www.mdpi.com/1422-0067/22/12/6305
Aberrations of x-Jun N-terminal kinases (JNKs) (MAP3K1, TRAF7) were also identified. Activation of the PI3K pathway and suppression of the NOTCH pathway are present in MCCs. […] In fact, oncogenic transformation by MCPyV requires two molecular events: integration of the MCP genome into the human genome and truncation of LT that makes the virus non-replicating. […] tLT preserves the pRB1-binding domain (LXCXE motif), which binds the cellular tumor suppressor retinoblastoma-associated protein (RB1 gene) and thereby releases elongation factor 2 (EF2), promoting progression to the S phase of the cell cycle. […] Expression of the C-terminal 100 amino acids inhibits the growth of MCPyV+ MCC, but the mechanism is not known. […] ST expression is required in the development of MCPyV+ MCC. ST protein plays a significant role in promoting mitogenesis and cell proliferation by upregulation of the PI3K-AKT-mTOR signaling pathway, which initiates cap-dependent translation.
#6 Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies
https://www.mdpi.com/1422-0067/22/12/6305
The PI3KâAKTâmTOR pathway is known to be overactivated in MCCs. […] The presence of chromosomal abnormalities is correlated with a larger size of MCC and an increased risk of metastases. They are more frequently observed within virus-negative than virus-positive MCCs. […] The mutational tumor burden of Merkel cell carcinoma varies significantly between virus-negative and virus-positive MCCs. MCPyV- MCCs have a higher overall mutational rate with the median of 1121 somatic single nucleotide variants (SSNVs) compared to 12.5 SSNVs in MCPyV+ MCCs.
#6 Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies
https://www.mdpi.com/1422-0067/22/12/6305
Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in 60â80% of MCC cases as integrated within the genome and is considered a major risk factor for MCC. […] Viral negative MCCs have a high mutation burden with a UV damage signature. Aberrations occur in RB1, TP53, and NOTCH genes as well as in the PI3K-AKT-mTOR pathway. […] In the process of non-viral-mediated carcinogenesis, ultraviolet radiation damages DNA. MCPyV- MCCs contain numerous DNA mutations caused by UV damage, whereas MCPyV+ MCCs have an incorporated viral genome and few mutations with âUV signatureâ. […] The median mutation burden in MCPyV- MCCs is estimated to be 1121 somatic single nucleotide variants (SSNVs) per exome with frequently downregulated RB1 and TP53.
#7
https://journals.lww.com/amjdermatopathology/fulltext/2024/11000/merkel_cell_carcinoma_case_reports_with_merkel.13.aspx
Merkel cell carcinoma (MCC) is known as a rare and highly malignant neuroendocrine skin cancer and often occurs in the sun-exposed parts of the elderly individuals. […] The pathogenesis of MCC is still not fully clarified. It is known that the pathogenesis may be a multifactorial process, including immunosuppression, UV damage to the skin (virus negative), and Merkel cell polyomavirus (MCPyV) infection. […] As for the pathogenesis of MCC, it is still not fully clarified. It is known that immunosuppression, UV damage to the skin (virus negative), and MCPyV might be involved in the pathogenesis of MCC. […] Among these oncogenesis factors, MCPyV plays a particularly important role. MCPyV, 1 of the polyomaviruses, is an unenveloped double-stranded DNA virus with a circular genome. Large T antigen (LT) and small T antigen (ST) are 2 important components.
#7
https://journals.lww.com/amjdermatopathology/fulltext/2024/11000/merkel_cell_carcinoma_case_reports_with_merkel.13.aspx
LT directly binds to and inhibits RB, which is a transcriptional repressor that acts as a guardian of G1/S cell cycle checkpoints. RB inactivation is a key molecular event entering the S phase. […] Therefore, the inactivation of RB by LT enables MCCP tumor cells to avoid growth inhibition. […] ST encodes a unique region that is essential in mediating ST-host protein interactions. […] LT and ST played crucial roles in the MCPyV oncogenesis of MCC. […] The MCPyV oncogenic hypothesis requires 2 fundamental elements: integration of the viral genome into the host genome and truncation of LT so that the viral genome cannot replicate. […] The extremely low probability that the virus mutates and no longer replicates at the same time could explain why MCC is rare and MCPyV infection is common.
#7
https://journals.lww.com/amjdermatopathology/fulltext/2024/11000/merkel_cell_carcinoma_case_reports_with_merkel.13.aspx
MCCP and MCCN not only have great differences in gene mutation but also have quite different prognoses. Studies have found that patients detected with antibodies to MCPyV oncoprotein had a better prognosis. […] Testing for the MCPyV at the onset of MCC is recommended, which is helpful in predicting the prognosis of patients.
#8 JMIR Dermatology – Merkel Cell Carcinoma on the Face: Case Report
https://derma.jmir.org/2024/1/e56658
Merkel cell carcinoma (MCC) is a rare primary neuroendocrine skin tumor that presents as a flesh-colored or bluish-red nodule on the face, neck, or head. Long-term ultraviolet radiation exposure and Merkel cell polyomavirus are associated with MCC pathogenesis. […] UV exposure and immunosuppression are the 2 primary etiological factors besides polyomavirus linked to an elevated risk of MCC. […] Another similar case was reported in 2023 in an immunocompromised patient with diabetes and hepatitis B, suggesting that decreased immune surveillance in these patients results in increased viral replication and integration in the progenitor cells of MCC. […] Prompt management and treatment of MCC is essential because if left untreated, it can spread to other parts of the body and can also metastasize to lymph nodes and other organs. […] MCC is distinguished by violaceous, red intradermal nodules in sun-exposed locations. MCC of the skin is an aggressive lesion with a high risk of metastasis and recurrence; long-term (5-year) survival rates range from 18% to 57%.
#9 Merkel Cell Carcinoma – Bezmialem Science
https://bezmialemscience.org/articles/merkel-cell-carcinoma/doi/bas.galenos.2022.08760
Merkel cell carcinoma (MCC) is a rare tumor that arises from mechanoreceptor Merkel cells. Ultraviolet exposure, immunosuppression and Merkel cell polyoma virus play a significant role in tumor pathogenesis. […] Immunosuppression is thought to be an important risk factor for MCC. Immunosuppressed patients; especially those with hematological malignancy, HIV, autoimmune disease and organ transplants, are at high risk for developing MCC. […] In our patient, we think that both autoimmune diseases and their treatments play a role in the development of MCC by causing immunosuppression. […] The MCC is more common in white race and males over 65 years of age. Ultraviolet exposure, immunosuppression and Merkel cell polyoma virus (MCPyV) play a significant role in tumor pathogenesis. […] The MCCs develop regional metastases in a short period of time. At the time of the diagnosis, 73% of the patients have local lesions, 23% regional lymph node metastasis and 4% distant metastasis. The MCCs often metastasize to the dermis, liver, bones, brain and lymph nodes.
#10 What is the mechanism behind Merkel cell carcinoma development – VJOncology
https://www.vjoncology.com/video/tg8lq1dejtq-what-is-the-mechanism-behind-merkel-cell-carcinoma-development/
Isaac Brownell, MD, PhD of the National Cancer Institute, Bethesda, MD provides insight into the possible mechanisms of Merkel cell carcinoma development at the 2016 World Congress on Cancers of the Skin (WCCS) and the Congress of the European Association of Dermato-Oncology (EADO) in Vienna, Austria. […] Clinical and pre-clinical evidence shows that Merkel cell carcinoma is highly regulated by the immune system and this may be one of the reasons why Merkel cell carcinoma tends to present late in life. […] Dr Brownell suggests, it may be that with increased age there is senescence of the immune system, which weakens the immune system and may allow for Merkel cell carcinoma to initiate. […] Supporting this idea, in immunocompromised populations the rate of Merkel cell carcinoma are much higher.
#11 SciELO Brazil – Merkel cell carcinoma: epidemiology, clinical features, diagnosis and treatment of a rare disease Merkel cell carcinoma: epidemiology, clinical features, diagnosis and treatment of a rare disease
https://www.scielo.br/j/abd/a/QYKxwGcZTZtB5BFFtL39Kps/
The association of immunosuppression with increased risk of MCC, in addition to some data that show a better prognosis in tumors with high infiltration of CD8+ T lymphocytes, has become a justification for immunotherapy use. […] The binding between PD-1 and its PD-L1 ligand leads to the inactivation and decreased proliferation of T cells. This process seems to be an important mechanism for the immune response inhibition by the tumor. […] These findings suggest that an immune response to viral antigens creates a local pro-inflammatory environment that stimulates PD-L1 expression in the tumor.
#12 Merkel cell carcinoma: epidemiology, clinical features, diagnosis and treatment of a rare disease | Anais Brasileiros de Dermatologia
https://www.anaisdedermatologia.org.br/en-merkel-cell-carcinoma-epidemiology-clinical-articulo-S0365059623000211
Immunohistochemistry, PCR, in situ DNA hybridization, or next-generation sequencing technologies are available methods to detect MCPyV in tumors, but these tests vary greatly in sensitivity and specificity. […] The association of immunosuppression with increased risk of MCC, in addition to some data that show a better prognosis in tumors with high infiltration of CD8+ T lymphocytes, has become a justification for immunotherapy use. […] The first study in this scenario was JAVELIN Merkel 200, an open, phase II multicenter clinical trial that investigated the clinical activity and safety of avelumab, an anti-PD-L1 antibody.
#13 Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches
https://www.mdpi.com/2072-6694/17/7/1212
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. […] The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells.
#13 Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches
https://www.mdpi.com/2072-6694/17/7/1212
Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TMEâthrough inhibition of ECM components, MMPs, or integrin signalingâmay enhance immune responses and improve clinical outcomes.
#14 Vascular invasion is an early event in pathogenesis of Merkel cell carcinoma | Modern Pathology
https://www.nature.com/articles/modpathol2010100
Vascular invasion is frequently seen in Merkel cell carcinoma tumor samples. Intravascular tumor cells were observed in 117 (93%) of the samples. The majority, 83 (66%), showed only lymphovascular invasion. Only blood vascular invasion was seen in four (3%) samples. In all, 30 (24%) samples displayed both lymphovascular invasion LVI and BVI. In only nine (7%) samples, no invasion was observed within the vascular structures. […] This is the first study demonstrating the high capacity of Merkel cell carcinoma to invade vascular, predominantly lymphovascular structures. Using specific endothelial markers, we found that intravascular tumor invasion is very common in Merkel cell carcinoma; lymphovascular invasion and/or blood vascular invasion was seen in 93% of the samples. It seems that lymphovascular invasion is an early event in Merkel cell carcinoma tumorigenesis, observed already in very small, 5mm tumors. […] The high frequency of lymphovascular invasion demonstrated in this study may explain the extremely aggressive clinical behavior of Merkel cell carcinoma. This finding supports the notion that sentinel node biopsy has a function even in very small primary Merkel cell carcinoma tumors.
#15 Implication of IL6-positive Cancer-associated Fibroblasts in Merkel Cell Carcinoma Pathogenesis: A Possible Modulator of Immune Microenvironment | Anticancer Research
https://ar.iiarjournals.org/content/42/9/4359
Background/Aim: The role of cancer-associated fibroblasts (CAFs) in the pathogenesis of Merkel cell carcinoma (MCC) remains unknown. […] This study provides a possible therapeutic target to overcome resistance to immune therapies in MCC. […] The phenotypic and functional heterogeneity of CAFs in cancer progression has received considerable attention in current cancer research. However, subpopulations and the implications of CAFs in the pathogenesis of MCC are largely unknown. […] We found that an increased population of IL6-positive CAFs (IL6+CAFs) has a negative association with intra-tumoral CD8+ tumor-infiltrating lymphocytes (TILs) in MCC tissues and is related to poor prognosis of patients with MCC, indicating its potential as a cellular target in MCC therapy. […] IL6+CAFs may affect prognosis of MCC via modulating the TIME.
#15 Implication of IL6-positive Cancer-associated Fibroblasts in Merkel Cell Carcinoma Pathogenesis: A Possible Modulator of Immune Microenvironment | Anticancer Research
https://ar.iiarjournals.org/content/42/9/4359
High intra-tumoral CD8+TILs were significantly lower in patients with high IL6+CAFs than in patients with low IL6+CAFs. […] This finding indicates that IL6+CAFs may have inhibitory functions against the migration of CD8+T cells towards tumor cells. […] High IL6+CAFs may affect the TIME of MCCs by influencing the function of various effector cells in TIME, thereby resulting in poor patient prognosis. […] This type of research will provide possible cellular and molecular targets to overcome the immune therapeutic resistance of MCC.
#16 Pathogenesis of Merkel Cell Carcinoma | CoLab
https://colab.ws/articles/10.1007%2F978-3-642-05072-5_14
Despite a substantial research effort, the understanding of the molecular basis of MCC is still limited. […] Overexpression of the anti-apoptotic molecule bcl-2 was observed in three-fourths of MCC tumors in two independent studies. […] Inhibition of bcl-2 expression in vivo by antisense oligonucleotides in a SCID mouse/human tumor xenograft model resulted in tumor shrinkage. […] The expression of this anti-apoptosis protein is a common finding in many cancers and suggests one of its mechanisms to avoid cell death; however, the same antisense oligonucleotides when tested in a phase II trial, demonstrated only a very limited, if any, efficacy in patients with MCC. […] Moreover, bcl-2 overexpression does not illuminate the promitotic pathways that drive MCC.
#17 PD-1 Inhibitors Make Impact in Merkel Cell Carcinoma, But Unmet Needs Persist
https://www.onclive.com/view/pd-1-inhibitors-make-impact-in-merkel-cell-carcinoma-but-unmet-needs-persist
MCC incidence is increasing, with older white males at higher risk. The disease is often associated with Merkel cell polyomavirus. […] In 2008, Merkel cell polyomavirus (MCPyV) was first identified in MCC tissue; integration of MCPyV into the host genome is estimated to cause 80% of cases of MCC in Europe and North America. […] PD-L1 expression is also often present within MCC cells and the tumor microenvironment. […] Clinical factors that confer a poor prognosis include the presence of regional and distant metastases, a primary tumor diameter exceeding 2 cm and/or its extension beyond the dermis, a tumor location in the head/neck region, and an age above 75 years. […] Beyond PD-1 inhibitor monotherapy, there has been interest from investigators in combining these agents with other therapies to improve outcomes for patients with advanced or metastatic MCC.
#18 Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel | Journal for ImmunoTherapy of Cancer
https://jitc.bmj.com/content/10/6/e004742
Several studies have established the presence of MCPyV in the majority (80%) of MCC and antibodies that recognize MCPyV oncoproteins are found in approximately 50% of patients with MCC. […] IHC is essential to distinguish MCC from its mimics; since MCCs are considered neuroendocrine carcinomas which express a set of epithelial and neuroendocrine markers, IHC facilitates the pathological diagnosis. […] In recent years, efforts have been aimed at exploiting the presence of MCPyV oncoproteins in MCCs to develop targeted therapies for virus-positive MCC cancers. […] The regulatory approval of avelumab addresses an important unmet need in MCC treatment, and in fact 100% of the experts agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable, and that also EAP data have concrete clinical implications.
#19 Phase 1b/2a Trial Launches: Novel Cancer Therapy Combined With Keytruda for Merkel Cell Carcinoma | HURA Stock News
https://www.stocktitan.net/news/HURA/tu-hura-biosciences-inc-initiates-phase-1b-2a-study-of-i-fx-hu2-0-as-dkjb9p1zoi8z.html
TuHURA’s initiation of this Phase 1b/2a trial strategically addresses a critical unmet need in Merkel Cell Carcinoma by targeting patients with deep-seated tumors without cutaneous manifestations – approximately 30% of MCC cases currently ineligible for their planned Phase 3 study. […] The mechanism of action is particularly compelling – IFx-Hu2.0 functions as an innate immune agonist designed to overcome primary resistance to checkpoint inhibitors. Previous data demonstrated systemic anti-tumor responses (abscopal effect) when injected into accessible tumors, and this study extends that approach to internal organs. […] If feasibility and safety is demonstrated for IFx-Hu2.0 and Keytruda when radiologically administered to deep-seated tumors, we plan to extend enrollment to a variety of non-MCC cancers that are known not to respond or respond poorly to CPIs. Since the underlying biology of why tumors don’t respond to CPIs is for the most part the same, then the mechanism of how IFx-Hu2.0 overcomes that resistance to CPIs should be independent of the type of cancer treated.
#20 Immunotherapy for Merkel cell carcinoma: a turning point in patient care | Journal for ImmunoTherapy of Cancer
https://jitc.bmj.com/content/6/1/23
Merkel Cell carcinoma (MCC) is a rare but aggressive cancer, with an estimated disease-associated mortality as high as 46%. […] Recent advances in our understanding of the biology of MCC have created opportunities for novel therapeutic strategies and hope for improving treatment efficacy. For example, the discovery of the oncogenic Merkel cell polyomavirus (MCPyV) that is associated with approximately 80% of MCC cases has led to further investigations into whether dysregulated immune surveillance plays a role in MCC pathogenesis, and how best to generate anti-tumor immunity. […] In 2008, Feng and colleagues described an oncogenic Merkel cell polyomavirus (MCPyV), present in about 80% of MCC tumors. MCPyV creates a large T antigen that inactivates tumor suppressors p53 and RB. This discovery not only identified a causative factor for MCC, but also suggested a role for immune evasion in MCCs oncogenesis. […] The totality of these data provided a strong rationale for testing immune checkpoint blockers in patients with advanced MCC.