It has been previously reported by us that theincidence of hepatic metastases is greatly augmented by either direct hepatic trauma (3) or liverdamage induced by a variety of other modalitiessuch as alteration of hepatic blood flow (4), interference with reticuloendothelial function (7), orcirrhosis produced with carbon tetrachioride ,(8).In addition, growth of dormant tumor cells hasbeen stimulated by hepatic injury (5). The precisemechanism(s) whereby such damage enhancestumor growth is not known. However, the possibiity has been considered that damaged or regenerating liver accelerated tumor growth throughthe elaboration of a humoral factor similar to thatwhich has been noted (2, 18, 24) to influence liver

Supported by American Cancer Society Grant No. P-14@and U.S.P.R. Grants CA-05716and CA-05949.

Received for publication May 15, 1963.

regeneration following partial hepatectomy. Withthe use of parabiotic animals this concept was investigated (9). Mechanical damage or partial hepatectomy in one member of a parabiotic pair failedto affect the incidence of metastases in the liverof the other parabiont which had had an intraportal injection of Walker tumor cells. Metastases,however, did occur in thelivers of those uninjectedparabionts subjected to liver damage or partialhepatectomy. Thus, there was no evidence fromthese studies that damaged or regenerating liverinfluenced tumor growth via a humoral factor, butit was suggested that damaged parenchymal cellsin contact with tumor cells might be responsiblefor the enhanced growth of the latter.

Aside from a report by Schneyer (17), a seriesof investigations by Vasiliev (21—28),and a fewobservations by several others, little knowledge is

1651

Local Factors Affecting Tumor Growth

I. Effect of Tissue Homogenates*

BERNARD FISHER AND EDWIN R. FISHER

(Department of Surgery, Laboratory of Surgical Research, and the Department of Pathology,University of Pittsburgh, SChOOlof Medicine, Pittsburgh, Pennsylvania)

SUMMARY

Previous studies demonstrated thatliver damage produced by a variety of modalitiesenhanced the incidence and growth of experimentally induced hepatic metastases.Search for possible mechanisms responsible for this augmentation provided no evidencethat a humoral factor related to hepatic damage or regeneration was responsible. It wasconsidered, however, that direct contact of damaged cells with tumor cells could be afactor. Since little information was available relevant to the effect of normal or damaged cells upon adjacent neoplastic elements, studies were carried out, with tissuehomogenates, to provide an environment for tumor cells somewhat akin to that indamaged liver.

Homogenates of various organs from adult animals given injections either si.multaneously with tumor cells or at separate sites accelerated the onset and subsequentgrowth of tumor. Freezing or heating of tissues failed to eliminate this response, andspecies specificity was not a factor.

Injection of homogenate in one member of a parabiotic pair had a similar growthpromoting effect upon tumor growing in the other parabiont. Of particular interest wasthe occurrence of tumor at the site of homogenate injection in both single and parabiotic animals when this was separate from the location of tumor cell inoculation.

Speculation as to mechanisms responsible for these observations is entertained, andit is suggested that the tumor growth-promoting factor is a product of dead or dyingnormal cells rather than a humoral factor associated with regeneration.

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16592 Cancer Research Vol. 923, November 1963

available concerning the effect of normal or damaged cells upon adjacent neoplastic elements. Toobtain more information, attention has been directed toward an evaluation of the effect of tissuehomogenates upon tumor growth. Such homogenates were used to provide a milieu for tumorcells perhaps, in some respects, similar to that encountered in damaged liver.

MATERIALS AND METHODS

Female Sprague-Dawley rats, weighing 175—200gm., housed in individual cages, and permittedwater and Purina Laboratory Chow ad libitum,were used in all experiments. The Walker carcinoma, propagated in this laboratory since 1957and used in numerous other studies, was employed.The technic for preparation and intraportal injection of tumor cell suspensions was previously described in detail (10). Viability of tumor cells insuspension was checked by vital staining technics.Either 500,000 tumor cells were inoculated subcutaneously into the right lower quadrant, or 5,000cells were injected intraportally. When tumor cellswere injected into parabiotic rats they were alwaysinjected subcutaneously into the right lower quadrant of the member designated as rat A. It is to beemphasized that in every experiment each group,including controls, was given injections of the sametumor cell suspension so as to eliminate individualtumor variability.

Animals were made parabiotic by ce,lioanastomosis. Approximately 1 month after operationcross-circulation of each pair (designated as ratsA and B) was evaluated. Radioactive iodinatedserum albumin (RISA), 0.2—0.3 ml., containing1 sic. of I's', was injected into the femoral vein ofanimal A. Four hours later aliquots of blood sampies drawn from both animals A and B werecounted in a ‘ywell counter. Only those pairs with80—100per cent equilibration were used. Almostall animals were in this range.

Sterile technic was used in the preparation oftissue homogenates. The removed tissue wasweighed, mashed through a sterile sieve (80 mesh),and diluted with saline. In this fashion a homogenate of desired concentration was preparedready for injection. When tumor cells were injected with the homogenate, cell suspensions weremixed with the homogenate so that the desirednumber of cells was contained in 4 ml. of the suspension.

Heated homogenates were prepared by placingthe flask containing the 30 per cent suspension inboiling water for 10 minutes; frozen homogenatewas stored at —15°C. for 7 days before use. Bothwere brought to room temperature just prior to

the addition of the tumor cell suspension and injection.

Vernier calipers were used to measure the threedian@eters of the tumor to within 0.1 cm., and thesize of the tumor was expressed as the product ofthese three dimensions. Although frequently a tinynodule could be felt 2—3days before it reached ameasurable size, the time of onset of tumor wastaken as the day when measurement was first possible. This was consistent in general with the timewhen tumors measured 1 cm. Measurement wascontinued daily for the next 6 days. Beyond thistime tumors were frequently necrotic or hemorrhagic, so that measurement was inaccurate andmeaningless.

RESULTS

1. Subcutaneous inoculation of tumor celL, together with various tissue homogenates.—Onlyfourof 47 animals (9 per cent) had palpable tumors18 days following the subcutaneous injection of500,000 tumor cells on the right side of the abdo

men. At 20 days, 28 per cent demonstrated tumors.Because of similarity in results, control groupswere pooled. If, however, tumor cells suspendedin fresh rat liver homogenate were inoculated, 32per cent of the animals had tumor 11 days later,and by 13 days 100 per cent demonstrated neoplasms (Table 1). Not only did tumors appearearlier when injected with the liver homogenate,but their subsequent rate of growth was accelerated (Table 3).

To evaluate the specificity of rat liver in producing these findings, tumor cells suspended infresh 30 per cent homogenates of kidney, brain,skeletal muscle, and spleen were similarly inoculated. All resulted in an acceleration of the onsetof the tumor, and brain and spleen produced a likeeffect on the subsequent growth of the tumor (Tables 1 and 3). Of the various tissues employed,brain produced the best response both in relationto time of tumor onset and subsequent growth.Appearance of tumor was least rapid when spleenwas used. Subsequent tumor growth was slowestwith skeletal muscle homogenate.

Frurther evaluation of specificity was carried outby injecting tumor cells suspended in heated andfrozen rat liver and in fresh dog and rabbit liver(Tables 92and 3). Results with frozen rat liverwere similar to the results obtained with freshliver. Heated rat liver, although not so effectiveas the frozen, nevertheless accelerated the appearance and subsequent growth of tumor. Dog liverhomogenate accelerated the onset of tumor appearance, as did that from rabbit, but subsequentgrowth was only slightly more rapid in those re

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Days after@TC@@

injection @TCaloneTC

andliverTC

andkidneyTC

andbrainTC

andskeletalmuscleTC

andspleen11

1213151618200

00009

2832

9710010010010010050

5883

10010010010067

8310010010010010010

4080

1001001001000

027556464

100No.rats:

@47341261011

DaysafterTC*

injectionTCaloneTC

anddogliverTC

andrabbit

liverTC

andheated

ratliverFrozen

ratliver11

12141618200

0009

280

5083

1001001000

00

2575830

0507575

10041

100100100100

100No.

rats:4712121222

FISHER AND FISHER—Tissue Homogenates and Tumor Growth 1653

ceiving dog liver homogenate than in controls andless rapid when rabbit homogenate was employed.

2. Subcutaneous inoculation of tumor celLi andtissue homogenates at different sites (Table 4).—Toevaluate whether the above results could be obtamed when tissue was injected at a site separatefrom the tumor, homogenates were inoculated elsewhere. When either liver or spleen was injecteddaily (X 7) on the left side of the abdominal wall,left axilla, back, or intraperitoneally, tumors generally appeared more rapidly than was observedin tumor-inoculated animals receiving saline (controls). The injection of kidney homogenate on theleft side resulted in similar findings. Only the intraperitoneal injection of spleen homogenate failedto elicit a response. The rate of tumor growthfollowing its first appearance was no more rapidin these experiments than in control animals.

A surprising observation was the occasional

in the death of most animals immediately following injection. All surviving animals demonstratedtumor. Intraportal injection of homogenate either24 hours prior to or 24 hours after tumor cell injection failed to produce such a response. The useof 10 per cent homogenates prepared from theseorgans had no accelerating effect on tumor appearance or subsequent growth.

When as few as 250 tumor cells were inoculatedwith 30 per cent homogenate a fivefold increaseover controls was observed. Whereas nineteen of30 animals (63 per cent) in the former group hadtumors, only four of 30 controls (13 per cent)demonstrated neoplasms.

It was of interest that an increase in lung metastases for the most part paralleled that occurringin liver (Table 5).

4. Intraportal inoculation of tumor celLi and subcutaneous injection of honwgenate (Table 6).—Fol

TABLE 1

PER CENT OF ANIMALS WITH TUMOR FOLLOWING SUBCUTANEOUS INJECTION OF TUMOR

CELLs TOGETHER WITH FRESH RAT TISSUE HOMOGENATES

* TC denotes tumor cell. 500,000 tumor cells and 0.5 ml. of 30 per cent tissue homogenateinjected.

growth of tumor at the site of liver homogenateinjection when it was distant from that of tumorcell inoculation. This occurred when the homogenate was injected subcutaneously in the backor left side or intraperitoneally.

3. Intraportal inoculation of tumor cells withliver and spleen homogenate (Table 5).—When5,000 tumor cells in saline were inoculated intraportally, only 19 per cent of the controls demonstrated hepatic tumor 14 days later. When a similar number of tumor cells suspended in 30 percent liver homogenate was injected, 85 per centexhibited tumors which were larger than the control tumors. No difference was observed when thehomogenate was prepared from animals hepatectomized 24 hours previously. Similar homogenatesof spleen resulted in tumors in 100 per cent of theanimals. The use of kidney homogenate resulted

TABLE 2

PER CENT OF ANIMALS WITH TUMOR FOLLOWING SUBCU

TANEOUS INJECTION OF TUMOR CELls TOGETHER WITH

HEATEDAND FROZENRAT LIVERHOMOGENATESANDHETEROLOGOIJS TISSUE HOMOGENATES

a TC denotes tumor cell. 500,000 tumor cells and 0.5 ml. of30 per cent homogenate injected.

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Tissu..No.BATSDAYs153456I.

Control

II. Liver:A. FreshB. HeatedC. Frozen

m. Rabbitliver

IV. Dogliver

V. Kidney

VI. Muscle

VII. Brain

VIII.Spleen48

551222

10

12

12

12

6

115.4±2.2

5.5±4.08.2±5.28.3±4.8

1.3±0.9

2.5±1.8

2.5±2.2

2.9±2.2

3.2±1.8

4.9±5.07.9±4.6

16 ±7.019 ±9.622 ±8.8

2.5±1.1

7.4±6.7

6.6±5.1

6.5±4.6

12 ±5.2

10 ±8.313

± 7.6

28 ±1294 ±1043 ±18

5.4± 2.3

16 ±11

16 ± 9.0

11 ±7.2

23 ± 9.4

19 ±1620±

8.8

40±1740± 9.063±22

12± 7.1

25±13

24±12

19±11

43± 8.1

28±2229±

9.0

53±2370±1775±24

19±12

28±15

38±12

25±10

28±1229±

6.2

64±3794±2285±26

23±12

41±26

40±15

38±18

49±15a

Tumor size is given in cu. cm. ±standard deviation.

TABLE 4

PER CENT OF ANIMALs DEMONSTRATING TUMOR AT SiTE OF TUMOR CELL INJECTION. INOCULATIONSOF TUMOR CELLS AND OF TissuE HOMOGENATES WERE AT DIFFERENTSIms*DAYS

ATTZB

TC*DUECTIONSALINEINJBCTION

OP PBZPABATIONS FROM NORMALTISSUES.

LiverSpleen.KidneyLeft

sideLeft axillaBackmn@ pent.IAIft sideLeft axillaIntra pent.Leftside@:;

15171921230

002156450

172940637118

13815069690

22447278849

9365564640

38506367718

16425075850

082533500

576666

90No.rats:535516181124121221

Cancer Research Vol. 923, November 19631654

lowing inoculation of 5,000 tumor cells intraportally, repeated subcutaneous injection of liver orkidney homogenate failed to evoke a response. Theincidence of tumor 14 days after inoculation wassimilar to that in controls. To determine whetheror not liver tumors appeared earlier in such homogenate-treated animals, groups were sacrificed 5,7, 8, and 10 days after intrapoi'tal inoculation of50,000 tumor cells and subcutaneous injection ofliver homogenate. Tumors appeared no earlierthan in saline-injected control animals.

5. Eqect of injection of tissue homogenates in

parabiotic animok (Table 7).—Five hundred thousand tumor cells were injected subcutaneously inthe right side of the abdomen of animal A, andliver homogenate was injected daily (X7) subcutaneously into the left side of animal B. Tumorsappeared more rapidly in such animals than incontrols given injections daily of saline. The rateof subsequent growth was no different in the twogroups. It was interesting to note that tumors appeared and grew more rapidly in control parabioticanimals than in single controls.

Just as tumors were observed at the site of

TABLE S

GROWTH OF TUMOR SUBSEQUENT TO APPEARANCE FoLLOwING INOCULATiON OF500,000TUMORCELLSAND TISSUEHOMOGENATESSUBCUTANEOUSLY*

S All rats were given injections of 500,000 tumor cells (TC) subcutaneously in right lower abdomen.

All injections of homogenates(30per cent) and saline weremade subcutaneouslydaily, X7, except those stated to be intraperitoneal.

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Tiasvz HOMOGENATENo.RATS1'u..oa

INCIDENCE

.Liver Lung(per (per

cent)cent)I.

Saline

II. 10%Liverhomogenate

III. 80% Liver homogenate

IV. 80% Liver homogenate24 hoursafter partial hepatectomy

V. 10% Spleen homogenate

VI. 30% Spleenhomogenate

VII. 30% Liver homogenate 24 hoursafter tumor cell injection

Vm. 30% Liver homogenate 24 hoursbefore tumor cell injection70

20

59

20

20

20

27

2919

11

85

80

15

100

15

1418

45

47

70

55

40

7

S

DAYS AFTERTUMOR CELL

INJECTIONPi:*

CENTOP A)tIMAI@WITHTUMORSingle

controlParabioticcon

trol. tumorcells in “A'Parabiotic.

tumor cells in“A@and liver

in“B@'9

1113151719280

000

2760600

424566064929

3057657070

87No.rats:152523

TISSUE EOMOGENATENo.RATSINCIDENCE

OP

HEPATIC TUMOR

Per1@cent5A.

ControlsLiver homogenate

B. ControlsKidney homogenate22

29

80807

9

141815

20

161782

31

4648

FISHER AND FISHER—TUtU8 Honwgenates and Tumor Growth :i655

homogenate injections in single animals (“2,―above), so did they occur at the site of homogenateinoculation in the parabiotic rat.

DISCUSSIONThe observations that adult tissue homogenates

are neither organ- nor species-specific, are notaffected by heating or freezing, and are effectivein augmenting tumor growth when injected eithersimultaneously with tumor cells or at a separatesite are not entirely in accord with those of others

TABLE 6

INCIDENCEOFTUMORIN LivER AND LUNG14 DAYSAFTERINTRAPORTAL INOCULATION OF 5,000 TUMOR CElLS WITH

30 PERCENT LivER AND SPLEENHOMOGENATE

who have evaluated the effects of embryonal aswell as adult tissue cells on tumor growth. Schneyer(17) reported an acceleration of tumor growthfollowing injection of a suspension of mouse embryonal tissue mixed with tumor cells which failedto occur when tumor and adult cells were inoculated. Vasiliev (21—23)systematically studied theeffects of normal tissue upon the growth of implanted tumor cells and reported that embryonictissue stimulated the growth of different isologous,homologous, and heterologous tumors, but only if

TABLE 7

EFFECT OF INJECTION OF SO PER CENT LIVER H0M0GENATEIN ONEPARABI0TIcUPONGRowTH o@

TUMOR IN THE OTHER MEMBER

Single controls and parabiotic “A―rats given injections of500,000 Walker tumor cells subcutaneously.

0.5 ml. of SOper cent liver homogenate injected subeutaneously daily X7 in animal “B.―

a small amount of tumor tissues was transplanted.This stimulating capacity was lost upon heatingand deep-freezing. He also reported that heterologous embryonic tissue was ineffective and thatnormal adult rat tissue possessed only a weakstimulating capacity (muscle) or none at all (tes.tide). Further, embryonic tissue had no stimulating effect when injected into a site other than thatof tumor implantation or when injected before orafter tumor cell inoculation Timoshechkina (20)observed that injection of brain tissue emulsioninhibited tumor growth

In general, the findings of Révész(16), Marteland associates (11), and Paschkis (14, 15) are inagreement with our observations. Révészreportedthat a suspension of adult mouse liver had a stimulating influence on the growth of an admixedsniali tumor cell fraction, and Martel and associates observed that liver homogenates enhancedthe growth of the Novikoff hepatoma Followingcentrifugation the active fraction was found to bein the sediment. Paschkis (14), in a comprehensive

All rats weregiven injections intraportally of 5,000Walkertumor cells.

TABLE 6

INCIDENCEOFTUMORINLWERFOLLOWINGINTRAPORTALINocULATION o@ s,000 WALKER CELLs AND SUBCUTANEOUS INJECTION OF TISSUE HOMOGENATES (SO PERCENT) X 10

a No difference in size of positives.

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1656 Cancer Research Vol. 923, November 1963

review of factors in tissue which promote growth,reported that an aqueous extract of rat liverhomogenate, as well as some commercially available beef liver fractions, enhanced tumor growth.That the growth-promoting activity was destroyedby heat is in agreement with the findings of Teirand Ravanti (19) that the liver growth factor washeat-labile.

Our observations that homogenates, when injected together with tumor cells, accelerated tumorgrowth suggest that perhaps some specific factorfrom the tissue is present which either directlystimulates tumor cell proliferation or produces astromogenic reaction which aids in the establishment of the tumor. The latter explanation may bedismissed. Microscopic studies fail to identify sucha connective tissue response, and, further, theaugmentation of tumor growth when tumor cellsand homogenates were injected at different sitesminimizes the importance of such a reaction. Thisis in keeping with the conclusions of Vasiiev (22),who noted that connective tissue reactions inducedby active and inactive liver suspensions were similar and were probably not responsible for the localstimulatory effect. That a specific tumor cellstimulating factor is elaborated from damagedtissue cells must be considered as a possible mechanism. In this regard, these studies lend furthersupport to our previous observations in parabioticanimals (9) that the augmentation associated withliver damage is probably not due to the specifichumoral factor commonly associated with liverregeneration following partial hepatectomy. Infact, extensive investigation in this laboratory (6)on tumor-free animals has failed to support theconcept that such a specific humoral factor exists.The fact that tumor stimulation results under sucha variety of conditions seems to militate againstthe specificity of this factor. That the stimulationis the result of a product of dead or dying cells isplausible, as is the possibility that it is due to thefactor, described by Menkin (13), which is liberated by severely injured cells at the site of inflammation and which displays growth-promotingproperties.

Certainly, with the limited information available, further conjecture as to mechanisms involvedseems worthless. Since a large number of mastcells were noted at the site of homogenate injection, either when it was with the tumor or separately, the significance of their presence is underinvestigation.

Why subcutaneously injected homogenate failedto stimulate tumor growth in the liver but didstimulate tumor growth at a distant subcutaneoussite is unexplainable. Perhaps the stimulating

factor under such circumstances was not carriedto the liver via the blood but was transported bythe lymphatiô system—or, more likely, the difference might be related to the difference in sites oftumor growth.

Since it has been demonstrated (12, 25) thatinjected homogenized liver tissue may increase themitotic rate of the liver, it was considered thatperhaps the action of the homogenate injected wasnot directly on tumor cells but was mediated indirectly via the liver. Observations by us, not reported, like those of Blomquist (1), failed todemonstrate a hepatic mitotic response differentfrom saline control-injected animals when adultrat liver homogenate was employed. Thus, thismechanism of action seems to be minimized.

The unexpected growth of tumor at the site ofthe liver homogenate injection in single and parabiotic animals, when this was separate from theplace of tumor inoculation, was similar to our previous observations (9) relative to the occurrenceof hepatic metastases in those parabiotic membersnot subjected to intraportal tumor cell injection,but in which liver manipulation was performed.A valid explanation for this phenomenon is notavailable. However, it is suggested from otherstudies by us that, following inoculation, there isan almost immediate wide dissemination of tumorcells. These cells may, under ordinary circumstances, fail to grow, but, when coming into contact with dead or dying normal cells, it would seemthat a proper micro-environment is supplied fortheir stimulation and growth. More informationrelevant to this environmental effect is essentialand is the subject of continuing investigation.

ACKNOWLEDGMENTS

The technical assistance of Miss Elizabeth Saffer and Mrs.Edith Melczer is gratefully acknowledged.

REFERENCES1. BLOMQUIST,K. Growth Stimulation in the Liver and

Tumor Development Following Intraportal Injections ofLiver Homogenates in the Rat. Acts PathoL Microbiol.Scandinav., SuppL 121, 1957.

2. CHRISTENSEN,B. G., and JACOBSEN,E. Studieson LiverRegeneration.Acts Med. Scandinav., Suppl. 234,pp. lOS8, 1949.

S. FISHER,B., and FISHER,E. R. Experimental Studies ofFactors Influencing Hepatic Metastases. III. Effect ofSurgical Trauma with Special Reference to Liver Injury.Ann. Surgery, 150:751—44, 1969.

4. . The Effect of Alteration of Liver Blood Flow uponExperimental Hepatic Metastases. Surg. Gynecol., Obst.,112:11—18,1961.

5. . ExperimentalEvidencein SupportoftheDormantTumor Cell. Science, 130:918—19, 1959.

6. Fisuxie, B.; FISHER, E. K; and SAmie, E. InvestigationsConcerning the Role of a Humoral Factor in Liver Regeneration. Cancer Res., 23:914—20,1963.

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FISHER AND FISHER—Tissue Homogenates and Tumor Growth 1657

7. FISHER, E. R., and FISHER, B. Experimental Studies ofFactors Influencing Hepatic Metastases. VII. Effect ofReticuloendothelialInterference. Cancer Res., 21:275—80,1961.

8. — . ExperimentalStudies of Factors Influencing Hepatic Metastases. IV. Effect of Cirrhosis. Cancer, 13:860—64,1960.

9. . Experimental Studies of Factors Influencing Hepatic Metastases. XIII. Effect of Hepatic Trauma inParabiotic Pairs. Cancer Res., 23:896—900, 1963.

10. . Experimental Studies of Factors Influencing Hepatic Metast.ases. I. The Effect of Number of Tumor CellsInjected and Time of Growth. Cancer, 12:926—28, 1959.

11. MARTEL, E.; Durouit, D.; and Au@&aD, C. Recherche dela fraction hépatique responsable de l'action stimulatricedu foie sur le développement de l'hépatome de Novikoff.Compt. rend. Soc. de Biol., 151:642—43, 1957.

12. MCJTJNKIN, F. A., and BREUHAUS, H. C. Homologous Liver as a Stimulus to Hepatic Regeneration. A.M.A. Arch.Pathol., 12:900—908, 1951.

13. MENKIN,V. Cellular Injury in Relation to Proliferativeand Neoplastic Response. Cancer Res., 1:548—56, 1941.

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15. PASCRKIS, K. E.; CANTAROW, A.; GODDARD, J. J.; andZAGERMAN, J. Growth-promoting Activity of Liver Preparations and Other Tissue Preparations. Fed. Proc., 17:121,1958.

16. R@v@sz,L. Effect of Lethally Damaged Tumor Cellsuponthe Development of Admixed Viable Cells. J. Natl. CancerInst., 20:1157—86, 1958.

17. SCHNEYER, C. A. Effect of Normal Tissue Inocula on

Homologous Tumor Transplants. Cancer Res., 15:268—70,1955.

18. SMrrHE, R. L., and Moonz, R. 0. A Study of PossibleHumoral Factors in Liver Regeneration in the Rat. Surgery,44:561—69,1958.

19. TErn, R., and RAVANTI, K. Mitotic Activity and GrowthFactors in the Liver of the White Rat. Exp. Cell Res.,5:500—507, 1953.

20. TIMOSHECREINA, M. E. Changes in the Resistance toTransplantable Tumours under the Influence of Subcntaneous Injections of Brain Tissue Emulsions. Problems ofOncology, 6:661—65, 1960.

21. V@s.sIuEv, J. M. The Influence of Experimentally InducedChanges in the Local Environment of Grafted Cells uponthe Establishment and Growth of Homologous and Heterologous Tumor Transplants. Ann. N.Y. ACEd. Sd., 87:214—16,1960.

22. . The LocalStimulatoryEffect of Normal Tissuesupon the Growth of Tumor Cells. Biological Interactionsin Normal and Neoplastic Growth (Henry Ford HospitalInternational Symposium), pp. 299—509. Boston: Little,Brown & Co., 1962.

23. V@tsIuEv, J. M., and OLaHEYSKAJA, L V. Embryonic Tissue as a Stimulant of Tumor Homotransplant Growth.Problems of Oncology (English Translation), 4:575—79,

1958.24. VONFRIEDRIcH-FREESA,H., and ZAKI,F. G. Speziflsche

Mitose-Auslösung in normaler Rattenleber durch Serumvon partiell hepatektomierten Ratten. Ztschr. Naturforsch., 9B :594—97,1954.

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1963;23:1651-1657. Cancer Res   Bernard Fisher and Edwin R. Fisher  HomogenatesLocal Factors Affecting Tumor Growth: I. Effect of Tissue

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