Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.

The interaction of recruited immune effector cells and cancer cells within tumor microenvironment (TME) shapes the fate of cancer progression and metastasis. Many cancers including breast cancer, express a specific vacuolar ATPase (a2V) on their cell surface which acidifies the extracellular milieu helping cancer cell proliferation and metastasis. To understand the role of immune cell-associated-a2V during breast tumor pathogenesis, we knocked-out a2V (KO) from the hematopoietic stem cells (HSC) and generated breast tumors in mice. The a2V-KO mice developed faster growing, larger, and metastatic breast tumors compared to control mice. Further investigation of the TME revealed a significant reduction in the presence of CD4+ and CD8+ T cells in the a2V-KO tumors. Targeted RNA-Seq of the cells of the TME demonstrated that pro-inflammatory cytokines, death receptors, death receptor ligands, and cytotoxic effectors were significantly down-regulated within the a2V-KO TME. Interestingly, analysis of immune cells in the blood, spleen, and thymus of the non-tumor bearing a2V-KO mice revealed a significant decrease in CD4+ and CD8+ T cell populations. For the first time, this study demonstrates that inhibition of V-ATPase expression in HSC leads to a decrease in CD4+ and CD8+ T cell populations and thus promotes breast tumor growth and metastasis.

Mammary epithelium-specific inactivation of V-ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer.

Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell-associated vacuolar ATPase 'a2' isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis. Using a mammary gland-specific a2V-knockout model, we show that in the absence of a2V, breast tumors exhibit atypically soft tumor phenotype, less tumor rigidity, and necrotic tumor microenvironment. These tumors contain a decreased number of cancer cells at primary tumor site, but showed extensive metastases compared to control. Nanomechanical evaluation of normal breast tissues revealed a decrease in stiffness and collagen content in ECM of a2V-deleted breast tissues. Mechanistically, inhibition of a2V expression caused dispersed Golgi morphology with relocation of glycosyltransferase enzymes to early endosomes in mammary epithelial cells. This resulted in defective glycosylation of ECM proteins and production of compromised ECM that further influenced tumor metastasis. Clinically, in patients with cancer, low a2V expression levels in normal breast tissue correlated with lymph node metastasis. Thus, using a new knockout mouse model, we have identified a2V expression in epithelial cells as a key requirement for proper ECM formation in breast tissue and its expression levels can significantly modulate breast tumor dissemination. Evaluation of a2V expression in normal breast tissues can help in identifying patients with high risk of developing metastases.

A rare case of acyclovir-induced thrombocytopenia.

Acyclovir is used for its potent antiviral properties for the mucocutaneous herpes, herpes zoster, herpes encephalitis, and genital herpes simplex. The drug has a very wide distribution involving almost every organ of the body, with excretion into the urine. Urine analysis, kidney function, liver function, and complete blood counts are some of the monitoring parameters. The active triphosphate form of the drug inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA. Because the drug is only absorbed by the cells that are virus infected, acyclovir has minimal side effects at therapeutic doses. However, at high intravenous infusions, severe central nervous system (malaise), gastrointestinal (nausea/vomiting), renal (elevated blood urea nitrogen/creatinine), hepatic (elevated liver enzymes), and skin dyscrasias have been found to occur. There have been few case reports of bone marrow suppression and only one case report so far of acyclovir-related isolated thrombocytopenia. Whether there is any further association between acyclovir and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome is the next dilemma if such an association is established. Here, the authors present a case report of a 58-year-old man with acquired immune deficiency syndrome on highly active antiretroviral therapy who went into severe thrombocytopenia on starting acyclovir.

Altered expression of alpha-methylacyl-coenzyme A racemase in prostatic adenocarcinoma following hormone therapy.

alpha-Methylacyl-coenzyme A racemase (AMACR) is a sensitive and specific tissue marker for the diagnosis of prostatic carcinoma. However, limited data are available on AMACR expression in residual prostatic carcinoma following hormone therapy. We analyzed 64 residual or recurrent prostatic adenocarcinomas following hormonal therapy for the expression of AMACR using a monoclonal antibody (P504S) to AMACR. In 20 localized cases, AMACR staining was absent in 11 (55%), 1+ in 6 (30%), and 2+ or 3+ in 3 (15%). However, in 15 metastatic cases, AMACR was absent in 1 (7%), 1+ in 3 (20%), and 2+ or 3+ in 11 (73%). None of the 29 postradiotherapy cases showed complete absence of AMACR staining: 2 (7%) were 1+, and 27 (93%) were 2+ or 3+. AMACR expression was reduced significantly in the majority of posthormonal residual carcinomas, whereas in postradiotherapy and in hormone-refractory metastatic prostatic adenocarcinoma, AMACR expression was retained. Therefore, the diagnosis of residual prostatic carcinoma after hormonal therapy using AMACR immunostaining must be interpreted with caution. Furthermore, AMACR might have a role in the recurrence of prostatic adenocarcinoma after medical therapy.

Primary malignant melanoma of the urethra.

Primary malignant melanoma of the urethra is an aggressive neoplasm associated with a poor prognosis. The outcome is dependent on early diagnosis and surgical intervention. However, the diagnosis is often delayed as a result of difficulties related to differentiating this lesion from other disorders. Such difficulties result from the variety of clinical and pathologic presentations that are common to melanoma. We report a case of primary malignant melanoma of the urethra with subsequent retrograde seeding of the bladder initially diagnosed and managed as invasive urothelial carcinoma.