Профилактические и терапевтические последствия силибинин антиметастатических эффективности

Cancer metastasis

Metastasis is now known as an extremely complex, multi-step and multi-functional biological event that eventually leads to death of the cancer patients [5,6,11]. During metastasis, cancer cells acquire motility, invade locally and enter into the systemic blood circulation (intravasation), survive in the circulation, arrest in microvasculature and subsequently extravasate and grow at distant organs (Fig. 1) [2,9,12,13]. In this complex phenomenon of cancer cells dissemination, acquisition of motility and invasiveness are the first major events during which cancer cells shed many of their epithelial characteristics, undergo drastic cyotskeletal alterations and acquire highly motile and invasive mesenchymal phenotype [14,15]. These series of changes in cancer cells have been termed as epithelial-to-mesenchymal transition (EMT) and is reminiscent of the highly conserved and fundamental process of EMT that occurs during early embryonic development [10]. The role of EMT in cancer progression has been well established now, and presumed an indispensable component of metastasis by cancer cells [15]. Next, the motile and invasive cancer cells in the primary tumors detach, invade and intravasate into blood or lymphatic circulatory system (Fig. 1). In the circulation, cancer cells interact with platelets and leucocytes to create aggregates or emboli, which protect them from the shear stress as well as immune response of the body (Fig. 1) [13,16,17]. The formation of these aggregates by cancer cells also support their settling in the capillaries of distant organs, extravasation and initial growth at distant organ site (Fig. 1) [9,18]. Once established at the distant metastatic site, many cancer cells recapitulate the differentiated phenotype of the primary tumors through a process called mesenchymal-to-epithelial transition (MET) [8,15]. Therefore, the important steps that enable metastasis appear to be reversible indicating the existence of dynamic components in human tumor progression.

One of the peculiar features of cancer cells is their propensity to metastasize to specific organ/s [19]. For example, prostate cancer cells mainly metastasize to bones; advanced colon cancer cells frequently spread to liver; lung cancer cells settle in adrenal glands, liver, brain and bone; melanomas migrate to liver, brain and skin; and breast cancer cells preferentially metastasize to lung and bones. Over a century ago, Stephen Paget first reported a non-random pattern of metastasis of cancer cells to certain organs while analyzing autopsy records of 735 women who endured breast cancer [13,19]. He proposed “seed and soil hypothesis”, in which he compared the metastasis of cancer cells to the dispersal of the seeds by plants. He postulated that seeds (‘cancer cells’) can grow only in a congenial soil (‘specific distant organ microenvironment’). According to this theory, osteotropic cancer cells like breast, prostate or lung, possess certain intrinsic properties that enable them to grow in the bone; and the bone microenvironment provides a fertile soil for their growth. This theory, which placed main emphasis on the compatibility between metastatic cancer cells and their microenvironment, was contested by James Ewing, who alternatively proposed that metastatic propensity of cancer cells is mostly dictated by circulatory patterns, and that metastasizing cancer cells would settle in organ/s to which they have the maximum vascular access [19]. Subsequent analyses of patterns of metastatic spread showed that although regional recurrences are highly dependent on the efficiency of vascular perfusion, distant metastatic recurrence for most cancers is non-random phenomenon, with no correlation with anatomically defined patterns of lymphatic or hematogenous circulation [20,21]. For example, Batson and others showed that vertebral venous system enables cancer cells from the pelvic region and breast to by-pass the pulmonary circulation, and could be responsible for the high propensity of breast and prostate cancer cells to produce metastasis in the axial skeleton [22,23]. However, this explanation alone does not explain the high incidence of metastasis of these cancer cells to other bones and organs. Recent molecular studies have identified the unique genetic signatures in cancer cells that mediate their organ-specific pattern of metastatic colonization [11,24–26]. Thus, Paget’s “seed and soil hypothesis” has still prevailed, and currently the molecular determinants of both seed and soil (tumor and its microenvironment) are rigorously investigated.

Now it is well appreciated that the interaction between cancer cells and their local microenvironment is crucial towards each step of cancer progression including their metastasis [9,27]. The success of metastasis is considered to be dependent on the cumulative ability of cancer cells to appropriately respond to the distinct microenvironment at each step in the metastatic cascade starting from primary tumor growth to final metastatic site (Fig. 1). The tumor microenvironment comprises diverse cell populations including endothelial cells of the blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells (BMDCs) including macrophages, myeloid-derived suppressor cells, monocytes and mesenchymal stem cells. These vast variety of cells play vital role in tumor growth, angiogenesis, invasion, intravasation, immune-suppression and distant metastatic growth [9]. Beside these cells, at distant site, cancer cells also interact with the local cellular components, invariably to its own advantage. For example, after extravasation into bone, breast cancer cells interact with osteoclasts and promote their osteoclastic activity towards greater bone resorption [13]. The local bone resorption debulks the bone, thereby providing space for cancer cells, and also releases survival factors and growth factors that promote breast cancer cells proliferation in their new home [13]. Recent studies suggest that interaction between cancer cells and their microenvironment need not be a local event, and the communication between cancer cells and their distant site microenvironment could occur even before actual metastasis [28,29]. Kaplan et al. showed that cancer cells at the primary site secrete factors which mobilize the bone-marrow derived hematopoietic progenitor cells (HPCs) to create favorable niche (termed as ‘premetastatic niche’) at the target distant organs before the arrival of metastatic cancer cells [28]. However, few other studies contradict this role of primary tumors in metastasis and point that the presence of primary tumor inhibits metastasis, while the removal of primary tumor promotes metastatic growth [30,31]. These disparate studies further suggest the complexity of cancer metastasis as well as the need for more studies to clearly understand the dynamic interaction between cancer cells and their microenvironment.

It’s now largely accepted that a sub-population of cancer cells called ‘cancer stem cells (CSCs)’ are primarily responsible for the initiation and growth of most of the cancers [32,33]. Recent studies suggest that stem cell population not only sustains the growth as well as heterogeneity of the primary tumors by deregulating the balance between ‘self-renewal’ and ‘differentiation’ but also their dissemination into surrounding tissues as well as distant organs [7,33,34]. It is believed that only cancer stem-like cells possess the necessary genetic plasticity to adapt to ever-changing microenvironment during the different steps of metastasis. This argument is supported by the fact that only a minute population of circulating cancer cells (probably less than 0.01%) has the ability to establish successful metastasis [9,35,36]. It has also been proposed that the EMT in cancer cells not only provides motility and invasiveness but also increases the stem cell-like characteristics of metastasizing cells [7,8,37]. The exact role of cancer stem cells or stem-like cells in metastasis is still being scrutinized but this concept further enhances the degree of complexity of this biological phenomenon.

As summarized above, metastasis is an extremely complex phenomenon and is critical in our efforts to lower the cancer-associated morbidity and mortality; however, treating patients with advance metastatic stage has remained a big challenge. Currently, chemotherapy, radiotherapy, hormone therapy, biological therapy, surgery or a combination of these therapies is employed to treat advance stage cancer patients. But in most cases, these therapies either alone or in combinations provide only a marginal or no survival benefit [38–40]. The clinical effectiveness of most of these therapies is constrained by the fact that during metastasis cancer cells spread to different organs, which incidentally also cause greater systemic toxicity. Further, current diagnostics have limited capability to identify the extent and spread of micro-metastasis in the body, thereby, making it practically impossible to fully wipe-out metastatic cells from the body. Furthermore, due to significant toxicity, the application of current therapeutic regimes is limited by the patient’s age or overall health, and in such situations patients have limited treatment options, if none. Not only current therapeutics have inadequate effectiveness, the cost of these treatments is exorbitant putting a great burden on the state exchequer. The finance side of treating the advance metastatic stage of the disease is relatively critical in developing economies with scant resources, and most of the treatments remain out of the reach of the patients [41,42]. Overall, the ineffectiveness, significant toxicity issues and exorbitant cost associated with current treatment regimes demand a fresh look at our approaches toward treating the advanced metastatic stage of cancer.

There are increasing evidences that nutraceutical agents are important in the prevention and intervention of cancer [43–48]. There are evidences that dietary/non-dietary agents and life style not only determine the cancer incidences but could also affect growth and progression or aggressiveness of the cancer cells [43,49–52]. The use of nutraceutical agents in prevention and intervention of metastasis is very attractive based upon the facts that these agents are already in human use and have limited or no-toxicity issues; target multiple events associated with metastasis through several mechanisms thereby limiting the chances of developing resistance by cancer cells; and are comparatively economical and could be used practically even in aged patients or in patients with compromised health. Overall, the list of nutraceuticals agents with efficacy against cancer metastasis is growing steadily and few of these agents have already entered the clinical phase [44,53–56]. The focus of present review is on the anti-metastatic efficacy of one such nutraceuticals agent, namely Silibinin (Fig. 2).